The GlaxoSmithKline group of companies

FDA ADVISORY COMMITTEE Briefing Document for Use of FLOVENT DISKUS and
ADVAIR DISKUS in COPD

**Document Number: RM2001/00294/00**

**For FDA Advisory Committee Meeting - January 17, 2002**

  ----------------------- -----------------------------------------------
  Sponsor:                GlaxoSmithKline

  Date of Report:         November 20, 2001
  ----------------------- -----------------------------------------------

The internal studies described herein were performed in compliance with
Good Clinical Practices and Glaxo Wellcome Standard Operating Procedures
for all processes involved, including the archiving of essential
documents.

Copyright 2001 the GlaxoSmithKline group of companies. All rights
reserved.

EXECUTIVE SUMMARY

# Introduction {#introduction .NoNum:Head2}

The contents of this briefing document review the clinical information
available in support of fluticasone propionate (**FLOVENT**[^1]
**DISKUS**[^2]**)** and the combination product containing fluticasone
propionate (FP) and salmeterol (**ADVAIR**[^3] **DISKUS)** for the
maintenance treatment of COPD, including chronic bronchitis and
emphysema. While a regulatory submission for salmeterol (**SERVENT**[^4]
**DISKUS)** in COPD was also included as part of the development program
for **FLOVENT** and **ADVAIR** **DISKUS**, the FDA has advised that it
will not be a subject for deliberation during the advisory committee
meeting. Results from the **SEREVENT** **DISKUS** treatment group in
this briefing document are presented for completeness and to allow for
comparisons between treatments.

Salmeterol xinafoate (SAL) is a long-acting inhaled
beta~2~-adrenoreceptor agonist available as two formulations in the US
(**SEREVENT** Inhalation Aerosol and **SEREVENT** **DISKUS**) for
treatment of asthma. In the US, **SEREVENT** Inhalation Aerosol is also
currently indicated for the maintenance treatment of bronchospasm
associated with COPD. To complement **SEREVENT** Inhalation Aerosol,
marketing approval is being sought for the 50mcg dose of **SEREVENT**
**DISKUS**, administered twice daily for treatment of COPD. To date,
**SEREVENT** has also been approved for the treatment of COPD in 31
countries outside the US. Worldwide, as of October 30, 2000 the exposure
to salmeterol inhalation aerosol or powder was estimated to be 12.7
million patient years for treatment of asthma and COPD.

Fluticasone propionate (FP) is a synthetic, trifluorinated
glucocorticoid with a high topical anti-inflammatory activity and
negligible oral bioavailability. FP is indicated for the maintenance
treatment of asthma as prophylactic therapy and is available as two
formulations in the US (**FLOVENT** Inhalation Aerosol and **FLOVENT**
**ROTADISK**[^5] for Inhalation via Diskhaler). **FLOVENT** **DISKUS**,
NDA 20-833, was approved in September 2000. No formulation of
**FLOVENT** is currently approved for the treatment of COPD in the US.
For treatment of COPD, marketing approval is sought for both the 250mcg
and 500mcg doses of **FLOVENT** **DISKUS**, administered twice daily. To
date, **FLOVENT** has been approved for the treatment of COPD in 67
countries outside the US. Worldwide, as of August 31, 2001 the exposure
to FP inhalation aerosol or powder was estimated to be 14.4 million
patient years for treatment of asthma and COPD.

**ADVAIR**, the combination of FP and salmeterol in a single inhaler, is
indicated for the maintenance treatment of asthma as prophylactic
therapy and is available as **ADVAIR** **DISKUS** in the US. No
formulation of **ADVAIR** is currently approved for the treatment of
COPD either in the US or any other country. For treatment of COPD,
marketing approval is sought for both the 250/50mcg and the 500/50mcg
strengths, administered twice daily. Worldwide, as of April 30, 2001,
the exposure to **ADVAIR** **DISKUS** was estimated to be 1.4 million
patient years for treatment of asthma and COPD.

# Rationale {#rationale .NoNum:Head2}

The rationale for the development of **FLOVENT** and **ADVAIR DISKUS**
for the treatment of COPD was based on sound scientific and clinical
grounds and can be summarized as follows:

-   COPD is defined by the American Thoracic Society as 'a disease state
    characterized by the presence of airflow obstruction due to chronic
    bronchitis or emphysema; the airflow obstruction is generally
    progressive, may be accompanied by airway hyperreactivity, and may
    be partially reversible.'

-   Emphysema and chronic bronchitis are complex pathophysiological
    conditions and frequently co-exist in the same patient. While
    neutrophilic inflammation is characteristic of the disease, a
    multitude of cells, mediators, and tissues have been implicated in
    its pathogenesis and contribute to its clinical severity.

-   COPD is a disease that exacts considerable toll on patients and
    society. It is currently the fourth leading cause of mortality in
    the US and projected to be the third by 2020. Morbidity from COPD
    also is rising with an estimated 668,363 hospital discharges in 1998
    and estimated annual cost to the nation in 2000 of 30.4 billion
    dollars.

-   The *Confronting COPD in America Survey* revealed that many patients
    with COPD experience substantial dyspnea, which impacts their
    activities of daily living and use of health care resources. About
    50% of patients reported that COPD limited their ability to work,
    sleep, perform household chores, or participate in social
    activities. Forty-five percent of patients required emergency care
    and 14% required hospitalization for their disease within the past
    year.

-   While smoking cessation is a primary objective of therapy,
    pharmacological therapy to alleviate airway obstruction, symptoms,
    and exacerbations is necessary for many patients even if they no
    longer smoke.

-   No medication has shown to modify disease progression in COPD, hence
    current approach to treatment advocated by guidelines consists of
    bronchodilator medications and ICS depending on disease severity.

-   Given the complexity of the disease, many patients require multiple
    medications to control the various pathophysiological processes
    responsible for the clinical manifestations of COPD.

-   While bronchodilators are the only agents currently approved by the
    FDA for COPD treatment in the US, considerable off-label use of ICS
    alone or with maintenance bronchodilators is occurring. Examination
    of prescription activity in the US indicates that approximately 40%
    of COPD patients are currently receiving ICS therapy. Additionally,
    46% of patients with COPD are currently receiving combination of two
    or more drugs of which 72% are prescribed an ICS as part of their
    regimen. Fifty-seven percent of these patients are being treated
    with maintenance bronchodilators and ICS.

-   Despite the availability of medications and guidelines advocating
    their appropriate use in the management of COPD, the control of COPD
    in the US remains sub-optimal.

-   For many patients, limitations such as convenience, tolerability,
    and effectiveness with current therapy may contribute to its under
    utilization leading to sub-optimal control of their disease.

-   Due to limited approved treatment options, many physicians have had
    to use ICS off-label without full knowledge of their benefit/risk.
    This may lead to patients receiving higher doses than necessary
    and/or reliance on frequent oral corticosteroid bursts with greater
    safety risks.

-   While many patients require treatment with multiple medications to
    improve clinical outcomes in COPD, this approach also increases
    treatment complexity contributing to patient confusion and
    non-adherence and may lead to greater morbidity.

-   Considering the serious public health consequences associated with
    COPD in the US, the availability and approval of new medications for
    its treatment should be regarded as a medical necessity.

-   Considerable scientific evidence supports the anti-inflammatory
    effects of ICS in the pathophysiology of COPD. Results from seven
    recent studies have demonstrated that ICS therapy in COPD is
    associated with reduction in airway inflammation (including
    neutrophils and CD8^+^ T-cells) as determined by lung biopsies,
    bronchoalveolar lavage, and sputum.

-   The administration of inhaled long-acting beta~2~-agonists and
    inhaled corticosteroids together provides broader as well as greater
    effects on cells, mediators, and tissues contributing to the
    pathophysiology of COPD than that achievable with either agent alone
    and provides a rationale for the clinical benefit of administering
    these two agents together.

-   The majority of clinical evidence indicates that inhaled
    corticosteroids including fluticasone propionate are beneficial in
    the treatment of COPD. While ICS therapy may not reduce the rate of
    lung function decline in patients with COPD, their use has been
    shown to improve lung function and reduce symptoms and exacerbations
    which are responsible for substantial morbidity in this disease.
    These findings support the widespread use of ICS in the treatment of
    COPD by US physicians and recommendations for their use in COPD
    treatment guidelines.

-   While clinical trial data examining concurrent therapy with inhaled
    long-acting beta~2~-agonists and corticosteroids together in the
    treatment of COPD are limited, results from a recent trial indicate
    that the addition of fluticasone propionate to salmeterol was
    associated with greater benefit than use of salmeterol alone.

-   The availability and approval of **FLOVENT** and **ADVAIR**
    **DISKUS** in the US will help physicians to make informed decisions
    regarding their use in the management of COPD and will help to
    address some of the limitations with current therapy. Its
    availability in a breath-actuated, easy to use delivery device may
    simplify COPD management leading to improved control of COPD for
    many patients.

# Clinical Pharmacology {#clinical-pharmacology .NoNum:Head2}

The clinical pharmacology program conducted in support of the use of
**FLOVENT** and **ADVAIR** **DISKUS** in the treatment of COPD build on
the information obtained as part of the development program for asthma.
Studies in healthy volunteers and patients with asthma had shown that
the pharmacokinetics and pharmacodynamic effects of administering
fluticasone propionate and salmeterol as a combination product were
comparable to that when these agents were administered alone. The
primary aim of the current program was to characterize FP
pharmacokinetics and pharmacodynamics in patients with COPD and to
compare these data to the available data for patients with asthma.

-   A dose-related increase in FP systemic exposure was observed in COPD
    subjects following an increase in dose from 250mcg to 500mcg twice
    daily with C~max~ averaging 53pg/mL and 84pg/mL, respectively.

-   No statistically significant reduction (10%) in serum cortisol was
    observed with FP 250mcg compared with placebo treatment in subjects
    with COPD. There was a small, statistically significant reduction
    (21%) in serum cortisol with FP 500mcg compared to placebo; however,
    this difference is not considered to be clinically significant.

-   Systemic exposure following inhaled administration of FP in COPD
    subjects was considerably lower compared to healthy subjects and
    similar to asthma subjects.

-   Systemic exposure following inhaled administration of FP with the
    **DISKUS** was considerably lower than the currently marketed CFC
    MDI.

-   The range of systemic exposure to FP in the COPD population was
    within the range observed in subjects with asthma. The range of
    serum cortisol values following drug administration was similar in
    COPD subjects and asthmatics and was generally comparable to placebo
    subjects.

-   These findings allow the extrapolation of the long-term safety data
    in asthma to patients with COPD.

# Design of Pivotal Studies {#design-of-pivotal-studies .NoNum:Head2}

The design and conduct of the development program to support the
efficacy and safety of **FLOVENT** **DISKUS** and **ADVAIR** **DISKUS**
for treatment of patients with COPD, including emphysema and chronic
bronchitis were conducted in consultation with the FDA. Three studies in
2054 subjects with COPD were performed and are summarized in the table
below.

  -------------- ------------- -------------- ------ ------------- ------------ ----------------
  **Study**      **\           **Treatment\   **\    **Duration\   **Baseline % **\
                 Objective**   (mcg BID)**    N**    (weeks)**     pred         Primary
                                                                   FEV~1~**     Efficacy**

  **FLTA3025**   Superiority   FP 250\        216\   24            41.0%\       Change from
                 of FP over    FP 500\        218\                 39.8%\       baseline at
                 placebo       PLA            206                  41.3%        endpoint in AM
                                                                                pre-dose FEV~1~

  **SFCA3006**   Superiority   FSC 500/50\    165\   24            40.9%\       Change from
                 of            FP 500\        168\                 41.4%\       baseline at
                 combination   SAL 50\        160\                 40.3%\       endpoint in AM
                 over FP &     PLA            181                  41.5%        pre-dose FEV~1~\
                 SAL\                                                           \
                 \                                                              Change from
                 Superiority                                                    baseline at
                 of\                                                            endpoint in 2h\
                 FP & SAL over                                                  post\--dose
                 placebo                                                        FEV~1~

  **SFCA3007**   Superiority   FSC 250/50\    178\   24            41.4%\       Change from
                 of            FP 250\        183\                 42.0%\       baseline at
                 combination   SAL 50\        177\                 41.9%\       endpoint in AM
                 over FP &     PLA            185                  42.1%        pre-dose FEV~1~\
                 SAL\                                                           \
                 \                                                              Change from
                 Superiority                                                    baseline at
                 of\                                                            endpoint in 2h\
                 FP & SAL over                                                  post-dose FEV~1~
                 placebo                                                        
  -------------- ------------- -------------- ------ ------------- ------------ ----------------

Each of the three studies was a randomized, double-blind,
parallel-group, placebo-controlled, multicenter trial designed and
conducted in an identical manner. Subjects were required to meet the ATS
definition of COPD, be at least 40 years of age, have a current or prior
history of ≥20-pack years of cigarette smoking, and have a history of
cough productive of sputum on most days for at least 3 months of the
year, for at least 2 years, that was not attributable to another disease
process. Subjects were required to have a baseline FEV~1~ \<65% of
predicted normal, but \>0.70L or FEV~1~ ≤0.70L and \>40% of predicted
normal with an FEV~1~/FVC ratio of ≤70%. Subjects also had to be
experiencing moderate dyspnea on the Modified Medical Research Council
(MMRC) Dyspnea Scale at Screening and have minimal symptoms of chronic
bronchitis (morning cough and sputum production) at Baseline.

Specific exclusion criteria were current diagnosis of asthma, current
use of oral or high-dose inhaled corticosteroids, abnormal clinically
significant ECG, need for long-term oxygen therapy, moderate or severe
exacerbation during the run-in, and any significant medical disorder
that would place the subject at risk, interfere with the evaluations, or
influence study participation.

Subjects who met the entrance criteria began a 2-week, single-blind,
run-in period with placebo treatment. All concurrent inhaled or oral
sympathomimetic or anticholinergic bronchodilators and inhaled or
intranasal corticosteroids were discontinued at the Screening Visit.
Concurrent theophylline therapy could be continued if a stable regimen
was maintained for 1 month prior to study entry and for the duration of
the study. Adjustments could be made to maintain a therapeutic dose of
theophylline during the study. All subjects received **VENTOLIN**[^6]
Inhalation Aerosol or nebules to use as needed for the duration of the
trial, including the 2-week run-in period.

Subjects who successfully completed the run-in period were assigned to
one double-blind treatment via the **DISKUS** BID for 24 weeks. Subjects
were evaluated weekly for the first 4 weeks of treatment (Weeks 1, 2, 3,
and 4), every 2 weeks until Week 8 (Weeks 6 and 8), and then at 4-week
intervals for the remainder of the study (Weeks 12, 16, 20, and 24).

FEV~1~ was chosen as the primary efficacy measure due to its wide
acceptance as a reproducible and objective indicator of disease severity
and prognosis in COPD. However, because beta-agonists and
corticosteroids treat different aspects of the disease, two different
FEV~1~ endpoints were measured for assessment of treatment efficacy:
pre-dose FEV~1~ for **ADVAIR** (FSC) and for FP, and 2-hour post dose
FEV~1~ for FSC and for SAL. Secondary measures of efficacy included
baseline and transition dyspnea index (BDI/TDI), chronic respiratory
disease questionnaire (CRDQ), chronic bronchitis symptoms questionnaire
(CBSQ), COPD exacerbations, morning PEF, daily **VENTOLIN** use, and
nighttime awakenings requiring **VENTOLIN**.

# Summary of Study Population Results {#summary-of-study-population-results .NoNum:Head2}

The results of the clinical trial support the following conclusions
about the study populations and their disposition during the conduct of
the trial.

-   Most subjects completed each individual study ([\>]{.underline}60%
    per treatment group). The percentages of subjects prematurely
    discontinuing the study were similar across the treatment groups.

-   Demographics, baseline characteristics, and baseline spirometry data
    were similar across the treatment groups in each of the three
    studies.

-   Medication adherence was high (\>95%) across the treatment groups in
    each of the three studies.

# Efficacy Results {#efficacy-results .NoNum:Head2}

Efficacy results from the three pivotal studies and the integrated
efficacy database for the COPD **DISKUS** clinical program demonstrated
the efficacy of all active treatments (FSC 250/50, FSC 500/50, SAL 50,
FP 250, and FP 500) following twice-daily treatment for 24 weeks in
subjects with COPD.

# FLOVENT DISKUS {#flovent-diskus .NoNum:Head3}

# Primary Efficacy Measure {#primary-efficacy-measure .NoNum:Head4}

**Pre-Dose FEV~1~**. In all three studies, treatment with FP was
associated with greater improvements in pre-dose FEV~1~ compared with
placebo. The estimated difference in pre‑dose FEV~1~ was significantly
greater for FP 500 in SFCA3006 (105mL) and FP 250 in SFCA3007 (112mL)
compared with placebo. In FLTA3025, a dose-related improvement in
pre-dose FEV~1~ was seen as FP 500 had a significantly greater
improvement than placebo (estimated difference = 57mL) while FP 250 did
not (estimated difference = 32mL). When data were integrated, the
estimated differences from placebo for FP 250 and FP 500 were 73mL and
85mL, respectively with 95% confidence intervals of (41mL, 105mL) and
(53mL, 118mL), respectively.

# Key Secondary Efficacy Measures {#key-secondary-efficacy-measures .NoNum:Head4}

**TDI**. A numerical dose response in TDI scores was demonstrated
between FP 250 and FP 500. In SFCA3006 and FLTA3025, treatment with
FP 500 resulted in significantly greater improvements in TDI scores when
compared with PLA at Week 1 and throughout treatment; estimated
differences at Endpoint = 1.1 and 0.8, respectively. No significant
differences were observed for treatment with FP 250 in SFCA3007 or
FLTA3025 at Endpoint.

**CRDQ**. In FLTA3025, increases in overall CRDQ score at Endpoint were
significantly greater for both FP 250 (5.1) and FP 500 (9.1) compared
with PLA (1.0) and approached the clinically meaningful threshold (≥10)
in the FP 500 group. In SFCA3007, increases in FP 250 (10.4) were
clinically meaningful and significantly greater compared with PLA (5.0).
In SFCA3006, increases in FP 500 (4.8) were similar to increases in PLA
(5.0).

**CBSQ GAS**. In SFCA3007, a significant difference was observed at
Endpoint for treatment with FP 250 compared with PLA (estimated
difference = 0.8). No other treatment differences of consequence were
observed in the individual studies. These results indicate that this new
instrument may not be sensitive for discerning treatment effects.

# Other Secondary Efficacy Measures {#other-secondary-efficacy-measures .NoNum:Head4}

**Incidence of COPD Exacerbation**. The incidence of COPD exacerbation
(any intensity) was comparable between the FP and PLA groups in the
three individual studies.

**AM PEF**. Increases in morning PEF for treatment with FP 250 and FP
500 were significantly greater compared with PLA in all the individual
studies.

**Daily VENTOLIN Use**. In SFCA3006 and FLTA3025, treatment with FP 500
resulted in significantly less Overall daily **VENTOLIN** use when
compared with PLA; the difference from PLA was only significant for
FP 250 in FLTA3025.

**Nighttime Awakenings Requiring VENTOLIN Use**. In the three individual
studies, treatment with FP 250 and FP 500 demonstrated significantly
fewer awakenings per night compared with an increase with PLA.

# ADVAIR DISKUS {#advair-diskus .NoNum:Head3}

# Primary Efficacy Measures {#primary-efficacy-measures .NoNum:Head4}

**Pre-Dose FEV~1~**. Treatment with FSC 250/50 and FSC 500/50 resulted
in significantly greater improvements in pre-dose FEV~1~ when compared
with SAL 50 at Endpoint; estimated differences = 69 and 67mL,
respectively. The estimated differences at Endpoint for treatment with
FSC 250/50 and FSC 500/50 compared with PLA were 161 and 159mL,
respectively. When data were integrated, the estimated differences at
Endpoint for treatment with FSC 250/50 and FSC 500/50 compared with
SAL 50 were 66 and 71mL, respectively, with 95% confidence intervals of
(19mL, 113mL) and (23mL, 119mL), respectively.

**Post-Dose FEV~1~**. Treatment with FSC 250/50 and FSC 500/50 resulted
in significantly greater improvements in post-dose FEV~1~ when compared
with FP 250 and FP 500 at Day 1 and throughout treatment; estimated
differences at Endpoint = 124 and 129mL, respectively. The estimated
differences at Endpoint for treatment with FSC 250/50 and FSC 500/50
compared with PLA were 214 and 231mL, respectively. Integrated data
supported the greater increases in each FSC group compared with the
corresponding strength of FP and with the placebo group.

# Key Secondary Efficacy Measures {#key-secondary-efficacy-measures-1 .NoNum:Head4}

**TDI**. Treatment with both FSC 250/50 and FSC 500/50 resulted in
dose-related improvement in mean TDI scores at Endpoint that were
significantly greater compared with PLA, estimated differences = 0.8 and
1.7, respectively. Treatment with FSC 500/50 also demonstrated a
significantly higher mean TDI score at Endpoint compared with SAL 50
(estimated difference = 1.2) and numerically greater compared with FP
(estimated difference = 0.7).

**CRDQ**. Treatment with both FSC 500/50 and FSC 250/50 resulted in
clinically meaningful increases (i.e., ≥10.0), from Baseline in overall
CRDQ score that were significantly greater compared with PLA.

**CBSQ GAS**. Treatment with both FSC 250/50 and FSC 500/50 demonstrated
significantly greater mean change from Baseline at Endpoint in GAS
compared with PLA, estimated differences = 0.6 and 0.7, respectively. No
other treatment differences of consequence were observed in the
individual studies.

# Other Secondary Efficacy Measures {#other-secondary-efficacy-measures-1 .NoNum:Head4}

**Incidence of COPD Exacerbation.** The incidence of COPD exacerbations
(any intensity or moderate/severe) for treatment with FSC was similar to
the incidence with SAL, FP, and PLA.

**AM PEF.** Treatment with FSC 500/50 resulted in a significant mean
increase in Overall AM PEF of 31.9L/min compared with mean increases of
16.8L/min and 12.9L/min for SAL 50 and FP 500, respectively, and
compared with a mean decrease (-2.7L/min) in the PLA group. Treatment
with FSC 250/50 resulted in a significant mean increase in Overall AM
PEF of 30.6L/min compared with mean increases of 14.7L/min and 11.3L/min
for SAL 50 and FP 250, respectively, and compared with a slight increase
(0.8L/min) in the PLA group.

**Daily VENTOLIN Use.** Significantly less Overall **VENTOLIN** use was
observed for treatment with FSC 250/50 and FSC 500/50 compared with PLA
and compared with FP 250 and FP 500, respectively. Mean changes from
Baseline in Overall **VENTOLIN** use were --1.0 and --1.2 puffs per day
for FSC 250/50 and FSC 500/50, respectively.

**Nighttime Awakenings Requiring VENTOLIN Use.** The FSC 250/50 and
FSC 500/50 groups had significantly fewer Overall nighttime awakenings
requiring **VENTOLIN** use compared with PLA. Overall mean changes from
Baseline were ‑0.12 and ‑0.04 awakenings per night for the FSC 250/50
and FSC 500/50 groups compared with increases of 0.02 and 0.10
awakenings per night with PLA, respectively.

# Onset and Duration of Effect {#onset-and-duration-of-effect .NoNum:Head3}

Efficacy as measured by pre-dose FEV~1~ for both FP 250 and FP 500 was
observed as early as Week 1. At Week 1, the estimated differences from
PLA for FP 250 and FP 500 were 53 and 61mL.

The bronchodilating effects of FSC 500/50 and SAL 50 were observed at
Day 1, indicating an early onset of effect. Twice-daily dosing was
supported by the maintenance of the effect for 12 hours.

No tolerance to the bronchodilator effect was observed over 24 weeks of
treatment.

# Efficacy in Population Subgroups {#efficacy-in-population-subgroups .NoNum:Head2}

Subgroup analyses based on gender, age, ethnic origin, ICS use at
Screening, bronchodilator response, and smoking status demonstrated
similar trends to the overall population with greater benefits observed
with **ADVAIR** vs. the individual components and with **FLOVENT** vs.
placebo. However, the magnitude of improvement was generally greater in
former vs. current smokers and reversible vs. non-reversible subjects.

# Safety Results {#safety-results .NoNum:Head2}

The following conclusion points summarize the clinical safety data from
the three controlled clinical studies (SFCA3006, SFCA3007, and
FLTA3025).

# Extent of Exposure {#extent-of-exposure .NoNum:Head4}

A total of 2054 COPD subjects were randomized to treatment in the three
US controlled clinical studies and received at least one dose of study
medication.

The mean extent of exposure was higher for the active drug treatment
groups compared with the placebo group.

# Adverse Events (AEs) {#adverse-events-aes .NoNum:Head4}

There was no evidence that the AE profile of either SAL or FP changed
when the two drugs were used in combination.

The overall incidence of AEs was comparable across the treatment groups.

The most commonly reported AEs, including upper respiratory tract
infection (URTI), headache, and musculoskeletal pain, were noted in
similar proportions of subjects across the six treatment groups. Throat
irritation, candidiasis, and hoarseness/dysphonia, all well-documented
side effects of inhaled corticosteroids, occurred with a higher
incidence in the FP and/or FSC groups as compared with the placebo or
SAL 50 groups.

# AEs Leading to Withdrawal {#aes-leading-to-withdrawal .NoNum:Head4}

AEs leading to withdrawal were reported by a relatively small proportion
of subjects across the treatment groups. Lower respiratory events
(mainly COPD exacerbation) were the most common AEs leading to
withdrawal.

# Deaths and Serious Adverse Events {#deaths-and-serious-adverse-events .NoNum:Head4}

In the controlled clinical studies, four subjects in the placebo group
died; no deaths occurred in the active drug treatment groups. None of
the deaths were considered by the investigator to be related to study
drug.

The incidence of SAEs was low and similar across the treatment groups.
As would be expected in subjects with COPD, SAEs mainly included lower
respiratory events (e.g., COPD exacerbation, pneumonia, and chest
symptoms). Only one subject experienced a SAE during treatment that was
considered by the investigator to be related to treatment (angina -
Subject 9060, SAL 50 group, study SFCA3006); this event was also
possibly attributed to a history of cardiovascular disease.

# Clinical Laboratory Test Results {#clinical-laboratory-test-results .NoNum:Head4}

There were no clinically relevant treatment effects observed on clinical
laboratory test results.

# HPA Axis Effects {#hpa-axis-effects .NoNum:Head4}

In SFCA3006 and SFCA3007, no consistent differences were noted when
examining abnormalities in short ACTH stimulation at Day 1 and Endpoint
across the treatment groups.

# Cardiovascular Safety {#cardiovascular-safety .NoNum:Head4}

Few subjects (43 of 2054, or 2%) had clinically significant changes in
ECG results. Overall, the incidence of clinically significant
abnormalities was lower for those treated with SAL (1%; nine of 688
subjects who received either SAL 50 or FSC 500/50; no clinically
significant abnormalities were noted for subjects treated with FSC
250/50) compared with placebo (3%; 17 of 576 subjects).

There was no evidence that administration of SAL or FP alone or in
combination increased the incidence of QTc prolongation.

The incidence of ventricular and supraventricular ectopic events and
cardiac rates in the placebo group was similar to the active drug
treatment groups at Screening and at Week 4. Only five subjects
experienced a significant change from their Screening Holter at Week 4
(one subject in the placebo group, one subject in the SAL 50 group, two
subjects in the FP 500 group, and one subject in the FSC 500/50 group).

# Vital Signs {#vital-signs .NoNum:Head4}

No effect of treatment was observed on pulse rate or on systolic and
diastolic blood pressure.

# Safety in Population Subgroups {#safety-in-population-subgroups .NoNum:Head4}

No clinically relevant treatment related differences were observed in
the safety profile for FSC and FP in population subgroups of gender,
age, ethnic origin, smoking status, and concurrent **VENTOLIN** and
methylxanthine use.

# Bone Mineral Density {#bone-mineral-density .NoNum:Head2}

Evaluation of information on BMD with FP therapy provides reassurance
that significant safety issues with the long-term use of FP in patients
with COPD are unlikely and can be summarized as follows:

-   Systemic corticosteroids are known to reduce BMD in areas of bone
    which has a high trabecular bone content such as the lumbar spine
    followed by femoral neck. These are the areas most prone to
    fractures confirming their clinical importance in assessing the
    impact of exogenous corticosteroid therapy.

-   Bone loss following treatment with oral corticosteroids at a dose of
    approximately 7.5mg per day can be seen as early as the first 6
    months of therapy. After 1 year of therapy with oral
    corticosteroids, decreases in bone mineral density of 5% have been
    observed.

-   Although systemic exposure due to inhaled corticosteroids is much
    less than with oral corticosteroids, the potential for an effect on
    bone mineral density has been suggested. Studies examining if
    inhaled corticosteroid in COPD patients impacts BMD have given
    conflicting results. Current evidence indicates that the use of
    inhaled corticosteroids is unlikely to result in an increase in the
    incidence of fractures in patients with COPD.

-   COPD patients have a number of factors which may confound the
    interpretation of BMD results: advanced age, smoking history,
    sedentary lifestyle, dietary deficiencies, potential hormonal
    (testosterone or estrogen) deficiencies, long-term systemic
    corticosteroid use, and/or use of anti-resorptive therapy.
    Imbalances in these variables between treatment groups and/or
    differences between inhaled corticosteroids in their propensity to
    cause systemic effects may explain some of the conflicting findings
    observed with trials evaluating the potential for inhaled
    corticosteroids to influence BMD in patients with COPD.

-   While BMD results with FP treatment in COPD are currently
    unavailable, the similar systemic exposure seen in patients with
    COPD compared to that seen in patients with asthma allows
    extrapolation of the long-term safety data with FP in asthma to
    patients with COPD.

-   No significant effects on BMD were seen in two separate trials
    comparing two years of treatment with FP 500mcg twice daily versus
    placebo in patients with mild asthma.

-   Three-out-of-three randomized, double-blind trials, which compared
    FP and BDP at therapeutically comparable dosages, found significant
    differences favoring FP vs. BDP on BMD at doses of FP as high as
    1000mcg/day for periods of up to two years. These results suggest
    that all inhaled corticosteroids may not have the same propensity to
    effect BMD.

-   These results from asthma are reassuring and suggest that the
    long-term use of **FLOVENT** and **ADVAIR DISKUS** in the treatment
    of patients with COPD is unlikely to be associated with BMD
    reductions. A large ongoing 3-year mortality trial in patients with
    COPD (TORCH, SCO30003) will also evaluate the effects of FP and
    **ADVAIR** on bone mineral density in a subset of patients.

# Benefit-Risk Conclusions {#benefit-risk-conclusions .NoNum:Head2}

The results from the clinical program indicate that both **FLOVENT** and
**ADVAIR** **DISKUS** have a favorable benefit to risk ratio for the
treatment of patients with COPD and can be summarized as follows:

-   The clinical program assessing **FLOVENT** **DISKUS** achieved its
    primary objective of demonstrating statistically significant and
    clinically relevant improvements in the primary measure of efficacy
    (pre-dose FEV~1~) compared with placebo.

-   The magnitude of improvements observed with **FLOVENT** **DISKUS**
    for the primary as well as secondary efficacy measures was
    comparable to that seen with salmeterol which is an approved agent
    for COPD indicating that fluticasone propionate provides clinically
    important benefits in the treatment of patients with COPD.

-   The clinical program also fulfilled the regulatory requirements for
    combination products in the US by achieving significantly greater
    improvements in both of the primary efficacy measures for treatment
    with **ADVAIR DISKUS** 250/50 and **ADVAIR DISKUS** 500/50 compared
    to salmeterol and FP (pre-dose and post-dose FEV~1~, respectively).

-   In addition to improvements in the primary measure of efficacy, both
    **FLOVENT DISKUS** and **ADVAIR DISKUS** provided clinical
    improvements in the secondary efficacy measures compared to placebo.
    Most of these achieved statistical significance for **FLOVENT**
    **DISKUS** and almost all achieved statistical significance for
    **ADVAIR** **DISKUS**.

-   **ADVAIR** **DISKUS** also provided significantly greater
    improvements for several secondary measures of efficacy compared to
    the individual agents (morning PEF and generally greater
    improvements in TDI and CRDQ) and numerical trends for other
    measures of efficacy. These findings suggest that treatment with
    both components is needed for control of the disease for many
    patients.

-   The benefits for treatment with either **FLOVENT DISKUS** or
    **ADVAIR DISKUS** were not associated with any unexpected,
    clinically significant topical or systemic adverse effects.

-   The long-term safety of FP therapy in patients with asthma is
    reassuring and suggests that the use of **FLOVENT** **DISKUS** and
    **ADVAIR** **DISKUS** in COPD is unlikely to be associated with BMD
    reductions.

-   The absence of clinically significant differences in response
    between the two doses suggests that **FLOVENT DISKUS** 250 or
    **ADVAIR DISKUS** 250/50 twice daily serve as the recommended
    starting doses for each medication.

# Proposed Indication and Dosage and Administration  {#proposed-indication-and-dosage-and-administration .NoNum:Head2}

The results from this clinical program support the following indication
and recommendations for dosage and administration.

-   **FLOVENT DISKUS** is indicated for the long‑term, twice‑daily
    maintenance treatment of COPD (including emphysema and chronic
    bronchitis). The proposed starting dosage for adults is 1 inhalation
    (250mcg) twice daily. For patients who do not respond adequately to
    the starting dose, increasing the dose to 500mcg twice daily may
    provide additional control.

-   **ADVAIR DISKUS** is indicated for the long‑term, twice‑daily,
    maintenance treatment of COPD (including emphysema and chronic
    bronchitis). The proposed starting dosage for adults is 1 inhalation
    (250/50mcg) twice daily (morning and evening, approximately 12 hours
    apart). For patients who do not respond adequately to the starting
    dose, replacing the 250/50‑strength with the 500/50‑strength may
    provide additional control. The proposed maximum recommended dose of
    **ADVAIR DISKUS** is 500/50mcg twice daily.

Patients who may, contrary to recommended use, double their dose of
**FLOVENT DISKUS** or **ADVAIR DISKUS** to treat worsening symptoms may
experience an increased incidence of pharmacologically predictable
adverse events associated with salmeterol or FP.

TABLE OF CONTENTS

Page

1\. INTRODUCTION AND BACKGROUND [6](#introduction-and-background)

1.1. Purpose and Content of the Briefing Document
[6](#purpose-and-content-of-the-briefing-document)

1.2. Overview of SEREVENT Development
[6](#overview-of-serevent-development)

1.3. Overview of FLOVENT Development
[6](#overview-of-flovent-development)

1.4. Overview of ADVAIR DISKUS Development
[6](#overview-of-advair-diskus-development)

1.5. Overview of the DISKUS [6](#overview-of-the-diskus)

1.6. Rationale Supporting the Use of FLOVENT and ADVAIR in the Treatment
of COPD
[6](#rationale-supporting-the-use-of-flovent-and-advair-in-the-treatment-of-copd)

1.6.1. Pathophysiology of COPD [6](#pathophysiology-of-copd)

1.6.2. Burden of Disease [6](#burden-of-disease)

1.6.3. Current Management of COPD [6](#current-management-of-copd)

1.6.4. COPD Patients on Prescription Therapy
[6](#copd-patients-on-prescription-therapy)

1.6.5. Limitations with Available Therapy
[6](#limitations-with-available-therapy)

1.6.6. Scientific Rationale [6](#scientific-rationale)

1.6.7. Clinical Rationale [6](#clinical-rationale)

1.6.8. Summary of Rationale [6](#summary-of-rationale)

1.7. Regulatory [6](#regulatory)

1.7.1. Proposed Indications and Dosage and Administration
[6](#proposed-indications-and-dosage-and-administration)

1.7.2. Summary of Significant FDA Interactions During the Clinical
Development Program
[6](#summary-of-significant-fda-interactions-during-the-clinical-development-program)

1.7.3. Non-US Marketing History [6](#non-us-marketing-history)

1.7.4. Withdrawals/Rejections [6](#withdrawalsrejections)

2\. CLINICAL PHARMACOLOGY AND BIOAVAILABLITY
[6](#clinical-pharmacology-and-bioavailablity)

2.1. Program Objectives [6](#program-objectives)

2.2. Study FLTA3025 [6](#study-flta3025)

2.3. Study FMS40243 [6](#study-fms40243)

2.4. FP Systemic Exposure [6](#fp-systemic-exposure)

2.5. Serum Cortisol [6](#serum-cortisol)

2.6. Relationship Between FP Systemic Exposure and Serum Cortisol
[6](#relationship-between-fp-systemic-exposure-and-serum-cortisol)

2.7. Clinical Pharmacology Conclusions
[6](#clinical-pharmacology-conclusions)

3\. DESIGN OF PIVOTAL STUDIES [6](#design-of-pivotal-studies-1)

3.1. Introduction [6](#introduction-1)

3.2. Study Design [6](#study-design)

3.3. Efficacy Measures [6](#efficacy-measures)

3.3.1. Primary Efficacy Measure [6](#primary-efficacy-measure-1)

3.3.2. Key Secondary Efficacy Measures
[6](#key-secondary-efficacy-measures-2)

3.3.3. Other Secondary Efficacy Measures
[6](#other-secondary-efficacy-measures-2)

3.4. Safety Measures [6](#safety-measures)

3.5. Statistical Methods [6](#statistical-methods)

4\. STUDY POPULATION OF PIVOTAL CLINICAL STUDIES
[6](#study-population-of-pivotal-clinical-studies)

4.1. Subject Accountability [6](#subject-accountability)

4.2. Demographic and Baseline Characteristics
[6](#demographic-and-baseline-characteristics)

4.3. Spirometry and Bronchodilator Response at Screening
[6](#spirometry-and-bronchodilator-response-at-screening)

4.4. Study Medication Adherence [6](#study-medication-adherence)

4.5. Summary of Study Population Results
[6](#summary-of-study-population-results-1)

5\. EFFICACY RESULTS [6](#efficacy-results-1)

5.1. FLOVENT DISKUS (FP) Efficacy [6](#flovent-diskus-fp-efficacy)

5.1.1. Primary Efficacy Measure: Pre-Dose FEV~1~
[6](#primary-efficacy-measure-pre-dose-fev1)

5.1.2. Key Secondary Efficacy Measures
[6](#key-secondary-efficacy-measures-3)

5.1.3. Other Secondary Efficacy Measures
[6](#other-secondary-efficacy-measures-3)

5.2. ADVAIR DISKUS (FSC) EFFICACY [6](#advair-diskus-fsc-efficacy)

5.2.1. Primary Efficacy Measures [6](#primary-efficacy-measures-1)

5.2.2. Key Secondary Efficacy Measures
[6](#key-secondary-efficacy-measures-4)

5.2.3. Other Secondary Efficacy Measures
[6](#other-secondary-efficacy-measures-4)

5.3. Onset and Duration of Effect [6](#onset-and-duration-of-effect-1)

5.3.1. FP 250 and FP 500 [6](#fp-250-and-fp-500)

5.3.2. FSC 500/50 and SAL 50 [6](#fsc-50050-and-sal-50)

5.4. Efficacy in Population Subgroups
[6](#efficacy-in-population-subgroups-1)

5.4.1. Smoking Status [6](#smoking-status)

5.4.2. Bronchodilator Response [6](#bronchodilator-response)

5.5. Summary of Efficacy [6](#summary-of-efficacy)

5.5.1. FP 250 and FP 500 [6](#fp-250-and-fp-500-1)

5.5.2. FSC 250/50 and FSC 500/50 [6](#fsc-25050-and-fsc-50050)

5.5.3. Onset and Duration of Effect [6](#onset-and-duration-of-effect-2)

6\. Safety Results [6](#safety-results-1)

6.1. Introduction and Data Organization
[6](#introduction-and-data-organization)

6.2. Extent of Exposure [6](#extent-of-exposure-1)

6.3. Adverse Event Experience in Clinical Trials
[6](#adverse-event-experience-in-clinical-trials)

6.3.1. Introduction [6](#introduction-2)

6.3.2. Incidence of Adverse Events [6](#incidence-of-adverse-events)

6.3.3. Adverse Events of Special Interest
[6](#adverse-events-of-special-interest)

6.3.4. Withdrawals Due to Adverse Events
[6](#withdrawals-due-to-adverse-events)

6.3.5. Deaths and Serious Adverse Events
[6](#deaths-and-serious-adverse-events-1)

6.4. Clinical Laboratory Tests [6](#clinical-laboratory-tests)

6.4.1. Laboratory Data Collection and Analysis
[6](#laboratory-data-collection-and-analysis)

6.4.2. Sponsor-defined Threshold Analyses for Potassium and Glucose
[6](#sponsor-defined-threshold-analyses-for-potassium-and-glucose)

6.5. Summary of Other Safety Assessments
[6](#summary-of-other-safety-assessments)

6.5.1. Cardiovascular Monitoring [6](#cardiovascular-monitoring)

6.5.2. HPA Axis Effects [6](#hpa-axis-effects-1)

6.5.3. Safety in Population Subgroups
[6](#safety-in-population-subgroups-1)

6.6. Summary of Safety from Clinical Trials
[6](#summary-of-safety-from-clinical-trials)

7\. Bone Mineral Density [6](#bone-mineral-density-1)

7.1.1. Introduction and Background [6](#introduction-and-background-1)

7.1.2. Inhaled Corticosteroids and BMD in patients with COPD
[6](#inhaled-corticosteroids-and-bmd-in-patients-with-copd)

7.1.3. Inhaled Fluticasone Propionate and BMD
[6](#inhaled-fluticasone-propionate-and-bmd)

7.1.4. Conclusions [6](#conclusions)

8\. Discussion of BENEFIT/RISK [6](#discussion-of-benefitrisk)

8.1. FLOVENT DISKUS [6](#flovent-diskus-2)

8.2. ADVAIR DISKUS [6](#advair-diskus-2)

8.3. Conclusions [6](#conclusions-1)

9\. Appropriate Use of FLOVENT DISKUS and ADVAIR DISKUS in the
Management of copd
[6](#appropriate-use-of-flovent-diskus-and-advair-diskus-in-the-management-of-copd)

9.1. Proposed Label: Indications, Dosage and Administration
[6](#proposed-label-indications-dosage-and-administration)

9.1.1. FLOVENT DISKUS [6](#flovent-diskus-3)

9.1.2. ADVAIR DISKUS [6](#advair-diskus-3)

9.1.3. Clinical implications of administration of more than one
inhalation of FLOVENT DISKUS or ADVAIR DISKUS
[6](#clinical-implications-of-administration-of-more-than-one-inhalation-of-flovent-diskus-or-advair-diskus)

9.2. Summary [6](#summary)

10\. References [6](#references)

Abbreviations Used in this Document

  ------------------- ---------------------------------------------------
  ACTH                adrenal corticotrophic hormone

  AE                  adverse event

  ALA                 American Lung Association

  AM                  morning

  ANCOVA              analysis of covariance

  ANOVA               analysis of variance

  ATS                 American Thoracic Society

  AUC                 area under the curve

  BAL                 bronchoalveolar lavage

  BD                  bronchodilator

  BDP                 beclomethasone dipropionate

  BDI/TDI             Baseline Dyspnea Index/Transition Dyspnea Index

  BHR                 bronchial hyperresponsiveness

  BID                 twice daily

  BMD                 bone mineral density

  bpm                 beats per minute

  BUD                 budesonide

  cAMP                cyclic adenosine monophosphate

  CBSQ                Chronic Bronchitis Symptom Questionnaire

  C~max~              maximum concentration

  C~min~              minimum concentration

  CNS                 central nervous system

  CO                  cross over

  COPD                chronic obstructive pulmonary disease

  CPAP                continuous positive airway pressure

  CRDQ                Chronic Respiratory Disease Questionnaire

  DB                  double-blind

  D/C                 discontinued

  DEXA                dual energy x-ray absorptiometry

  dL                  deciliter

  ECG                 electrocardiogram

  FDA                 Food and Drug Administration

  FEV~1~              forced expiratory volume in one second

  FP                  fluticasone propionate

  FSC                 fluticasone propionate and salmeterol combination
                      product

  FVC                 forced vital capacity

  GAS                 Global Assessment Score

  GI                  gastrointestinal

  GOLD                Global Initiative for Chronic Obstructive Lung
                      Disease

  GPRD                General Practice Research Database

  GS                  corticosteroid

  GSK                 GlaxoSmithKline

  HPA                 hypothalmic-adrenal axis

  HPLC                high-performance liquid chromatography

  ICD                 International Classification of Diseases
  ------------------- ---------------------------------------------------

Abbreviations Used in this Document (cont'd)

  ------------------- ---------------------------------------------------
  ICS                 inhaled corticosteroid

  ITT                 Intent-to-Treat

  LABA                long-acting beta~2~-agonist

  mcg                 microgram

  MCIC                minimum clinically important change

  MDI                 metered-dose inhaler

  mL                  milliliter

  mmHg                millimeters of mercury

  MMPs                matrix metalloproteinases

  MMRC                Modified Medical Research Council

  NDA                 New Drug Application

  NDC                 National Drug Code

  NHLBI               National Heart, Lung and Blood Institute

  OL                  open label

  PC                  placebo controlled

  PEF                 peak expiratory flow rate

  PLA                 placebo

  QTc                 corrected QT interval

  QTcB                QT interval with Bazett's correction

  QTcF                QT interval with Fridericia's correction

  RIA                 radioimmunoassay

  RR                  relative rate

  SAE                 serious adverse event

  SAL                 salmeterol

  SRBI                Schulman, Ronca, and Bucuvalas, Inc.

  SVE                 supraventricular ectopic

  t~1/2~              half life

  TIMP-1              tissue inhibitor of metalloproteinase-1

  URI                 upper respiratory inflammation

  URTI                upper respiratory tract infection

  US                  United States

  VE                  ventricular ectopic

  WHO                 World Health Organization
  ------------------- ---------------------------------------------------

# INTRODUCTION AND BACKGROUND

## Purpose and Content of the Briefing Document

The US Food and Drug Administration (FDA) Division of Pulmonary and
Allergy Drug Products has called for an Advisory Committee to meet on
January 17, 2002 to consider the benefit/risk of **FLOVENT**[^7]
**DISKUS**[^8] and **ADVAIR**[^9] **DISKUS** for the maintenance
treatment of COPD, including chronic bronchitis and emphysema.
**FLOVENT** **DISKUS** is a powder inhaler that contains fluticasone
propionate (FP), an inhaled corticosteroid. **ADVAIR** **DISKUS** is a
new inhaled combination powder formulation that contains FP and
salmeterol (SAL), a long acting beta~2~-agonist. While a regulatory
submission for **SERVENT**[^10] **DISKUS** in COPD was also included as
part of the development program for **FLOVENT** and **ADVAIR**
**DISKUS**, the FDA has advised that it will not be a subject for
deliberation during the advisory committee meeting. Results from the
**SEREVENT** **DISKUS** treatment group in this briefing document will
be presented for completeness and to allow for comparisons between
treatments; however, justification for the benefit/risk of **SEREVENT**
**DISKUS** in COPD will not be included.

This briefing document has been compiled by GlaxoSmithKline, Inc. to
serve as a review document for the Advisory Committee members. Included
are relevant clinical pharmacology, clinical efficacy and clinical
safety data for **FLOVENT** **DISKUS** compared with placebo and for
**ADVAIR** **DISKUS** compared with the FP, SAL and placebo. This
document also provides the rationale for combining FP and SAL to treat
patients with COPD and recommendations for appropriate use of each
product.

## Overview of SEREVENT Development

Salmeterol is available as two formulations in the US (**SEREVENT**
Inhalation Aerosol, NDA 20-236, approved February 1994; and **SEREVENT**
**DISKUS**, NDA 20-692, approved September 1997) for patients with
asthma.

In the US, the aerosol formulation (MDI) of **SEREVENT** received
approval for the maintenance treatment of bronchospasm associated with
COPD, including chronic bronchitis and emphysema. To complement
**SEREVENT** Inhalation Aerosol, marketing approval is being sought for
the 50mcg dose of **SEREVENT** **DISKUS**, administered twice daily for
treatment of COPD. As of May 31, 2001, **SEREVENT** has also been
approved for the treatment of COPD in 31 countries outside the US.

Worldwide, as of October 30, 2000 the exposure to salmeterol inhalation
aerosol or powder was estimated to be 12.7 million patient-years for
treatment of asthma and COPD.

## Overview of FLOVENT Development

Fluticasone propionate is indicated for the maintenance treatment of
asthma as prophylactic therapy and is available as two formulations in
the US (**FLOVENT** Inhalation Aerosol, NDA 20-548, approved March 1996;
and **FLOVENT** **ROTADISK**[^11] for Inhalation via **DISKHALER**[^12],
NDA 20-549, approved November 1997). **FLOVENT DISKUS**, NDA 20-833, was
approved in September 2000. Because the dose of an inhaled
corticosteroid should be adjusted to the severity of the disease,
approval was obtained for three strengths of **FLOVENT DISKUS** (50, 100
and 250mcg) to deliver the recommended doses of FP. To date, **FLOVENT**
has been approved for the treatment of COPD in 67 countries outside the
US.

No formulation of **FLOVENT** is currently approved for the treatment of
COPD in the US. For treatment of COPD, marketing approval is sought for
both the 250mcg and 500mcg doses of **FLOVENT DISKUS**, administered
twice daily.

Worldwide, as of August 31, 2001 the exposure to FP inhalation aerosol
or powder was estimated to be 14.4 million patient-years for treatment
of asthma and COPD.

## Overview of ADVAIR DISKUS Development

**ADVAIR DISKUS** (NDA 21-077) was approved for treatment of asthma in
August 2000. In order to allow the dose of an inhaled corticosteroid to
be adjusted to the severity of the disease, approval was obtained for
three strengths of **ADVAIR DISKUS** (100/50mcg, 250/50mcg and
500/50mcg) to deliver recommended doses of FP in combination with 50mcg
SAL.

No formulation of **ADVAIR** is currently approved for the treatment of
COPD either in the US or any other country. For treatment of COPD,
marketing approval is sought for both the 250/50mcg and the 500/50mcg
strengths, administered twice daily.

Worldwide, as of April 30, 2001, the exposure to **ADVAIR DISKUS** was
estimated to be 1.4 million patient-years for treatment of asthma and
COPD.

## Overview of the DISKUS

The **ADVAIR, SEREVENT** and **FLOVENT DISKUS** inhalers are the same
multidose powder inhaler device consisting of molded plastic containing
a foil strip with 60 regularly distributed blisters. A given device
contains a small quantity of SAL (micronized) alone, FP (micronized)
alone or the combination of the two, each blended with lactose. Each
blister contains 50mcg of SAL and/or either 250mcg, or 500mcg of FP made
up to 12.5mg with lactose. The foil strip consists of a formed base foil
with a peelable lid foil. Because each dose is pre-measured, consistent
dosing from the **DISKUS** Inhaler occurs across the range of
inspiratory flows generated by most patients.

The **DISKUS** Inhaler is robust and easy to use, requiring three steps
to take a dose; open, click, and inhale. The **DISKUS** device is
breath-actuated, generates minimal airflow resistance and does not
require special co-ordination of inhalation and actuation of the device.
These characteristics make the **DISKUS** the ideal delivery device for
treatment of COPD patients, many of whom have difficulty co-ordinating
the actuation-inhalation process, as well as low inspiratory flow
associated with severe COPD, i.e., FEV~1~ 20-30% predicted. The
**DISKUS** device also offers the advantage of a dose counter to improve
monitoring of dosing adherence.

## Rationale Supporting the Use of FLOVENT and ADVAIR in the Treatment of COPD

The rationale for the development of **FLOVENT** and **ADVAIR DISKUS**
for the treatment of COPD was based on several factors including the
pathophysiology of the disease, the scientific evidence of the effects
of ICS and inhaled long-acting beta~2~-agonists on the underlying
disease process, the clinical benefits associated with taking these
medications, and practical considerations related to convenience and
patient adherence which may help to address some of the limitations with
current therapy in the management of COPD.

### Pathophysiology of COPD

COPD is defined by the American Thoracic Society as 'a disease state
characterized by the presence of airflow obstruction due to chronic
bronchitis or emphysema; the airflow obstruction is generally
progressive, may be accompanied by airway hyperreactivity, and may be
partially reversible'. The etiology of COPD is poorly understood but
there are clear genetic (α1-antitrypsin deficiency; Mahadeva, 1998) and
environmental factors (cigarette smoke; Hogg, 1994) which contribute to
the expression of this disease.

Emphysema and chronic bronchitis are complex pathophysiological
conditions and frequently co-exist in the same patient. Emphysema is
associated with the destruction of the walls of the alveoli with
abnormal permanent enlargement of the airspaces distal to the terminal
bronchioles and loss of alveolar attachments. As a result, elasticity of
the lung tissue is lost, causing airways to collapse and obstruction of
airflow. Chronic bronchitis is associated with inflammation of the
respiratory bronchioles, enlargement of bronchial mucous glands
accompanied by dilation of gland ducts. Goblet cell size and number are
increased, and there may be both metaplasia and hypertrophy of airway
smooth muscle. As a result, there is plugging of the respiratory
bronchioles with muscle or mucous, and distortion due to fibrosis (ATS,
1995).

Persistent reduction in expiratory flow and a progressive deterioration
in lung function despite aggressive treatment characterize COPD.
Inflammation, fibrosis, goblet cell metaplasia, and smooth muscle
hypertrophy in terminal bronchioles, as well as loss of alveolar
attachments to bronchioles due to alveolar destruction are important
causes of airflow obstruction. Although expiratory airflow may improve
significantly with treatment, by definition, expiratory airflow will
never normalize and will progressively worsen with time. Patients with
COPD have shortness of breath, initially appearing as dyspnea on
exertion and then progressing insidiously. Typically, progressively
increasing productive cough and sputum production are also symptomatic
manifestations of COPD. Patients most often modify their lifestyles to
compensate for the dyspnea and activity limitation associated with
reduced expiratory airflow (Petty, 2000). In addition to these symptoms,
periods of acute deterioration due to viral or bacterial exacerbations
lead to considerable morbidity and mortality from the disease.

### Burden of Disease

The exact prevalence of COPD is not well characterized due to variable
definitions over time and a high proportion of undiagnosed disease;
however, COPD affects millions of individuals in the US and data suggest
that the prevalence is rising. The reported prevalence rate for chronic
bronchitis increased 58 percent between 1982 and 1996, from 33.9 per
1,000 to 53.5 per 1,000 persons (Adams, 1999). It is estimated that in
2001 as many as 21.7 million individuals in the US actually have some
form of COPD; only 6.5 million have been diagnosed with COPD and as many
as 15.2 million more individuals remain undiagnosed (unpublished
analysis of the NHANES III data, GSK, June, 2001)[^13].

COPD exacts considerable toll on patients and society. COPD is a
progressive disease and is one of the few major diseases with increasing
mortality. The age-adjusted death rate from COPD-related causes
increased 42 percent, from 14.0 per 100,000 in 1979 to 19.9 per 100,000
in 1998 (American Lung Association, 2001). COPD is currently the
fourth-leading cause of death (National Center for Health Statistics,
2001) and is projected to be the third-leading cause of death by the
year 2020 (Murray, 1996). In contrast, the age-adjusted death rate
attributed to all causes decreased by 18 percent and seven of the ten
leading causes of death experienced decreases in age-adjusted mortality
during this time.

COPD is also associated with considerable morbidity, which is also
increasing. Hospitalization for COPD-related illnesses and related costs
increased significantly from 1979 to 1998. An estimated 668,362 hospital
discharges due to COPD were reported in 1999, a discharge rate of 24.5
per 10,000 population (National Center for Health Statistics, 1998).
According to estimates, in 1993 the annual cost to the nation for COPD
was \$30.4 billion (NHLBI Chart Book, 1993). This included \$14.7
billion in direct health care expenditures, \$6.5 billion in indirect
morbidity costs and \$9.2 billion in indirect mortality costs.

To better characterize the current status of COPD in the US, a national
survey of public, patient and professional knowledge, attitudes and
behavior regarding COPD was conducted between August and November 2000
(ALA, February 2001). The *Confronting COPD in America* survey was
conducted by Schulman, Ronca and Bucuvalas, Inc. (SRBI), a national
public-opinion research firm. Dr. Stephen Rennard of the University of
Nebraska Medical Center served as an advisor. GlaxoSmithKline sponsored
the survey.

*Confronting COPD in America* is the largest and most comprehensive
survey of patients with COPD to date. Among the issues it explored were
the frequency and severity of symptoms, the burden of illness,
healthcare utilization, disease management and treatment, and quality of
life. Telephone interviews were completed with a national sample of 573
COPD patients. The sample was identified by systematically screening a
national sample of 26,880 US households to find patients 45 years and
older who had been diagnosed with COPD, emphysema or chronic bronchitis,
or whose symptoms matched a strict definition of chronic bronchitis. A
national sample of 203 physicians - 100 primary care physicians and 103
respiratory specialists - was also interviewed as part of the survey.

The *Confronting COPD in America Survey* revealed that many patients
with COPD are suffering from shortness of breath so severe that it
interferes with even their most basic daily activities and limits their
ability to work. When asked about the frequency of their symptoms during
their worst 3-month period in the past year, more than three-quarters of
the patients had been short of breath at least a few days a week and
more than half had shortness of breath every day or had been awakened at
night by coughing, wheezing or shortness of breath at least a few days a
week. The impact of breathlessness on every-day activities was also
striking. About three-fourths of patients were breathless when walking
up only one flight of stairs with 25% experiencing difficulty breathing
even when sitting or lying still and eight percent were too breathless
to even leave the house. Approximately 25% of the patients consider
themselves made invalids by their disease and 66% expect their condition
to get worse.

The survey also indicated that COPD had a considerable impact on
patients' activities of daily living and their use of health care
resources. Approximately, 50% of patients reported that COPD limited
their ability to work, sleep, perform household chores, or participate
in social activities. Almost three-quarters of patients see a doctor at
least a few times a year and nearly a quarter at least once a month for
their disease. Additionally, 14% of patients reported being hospitalized
overnight and 45% of patients required emergency medical attention for
their condition during the previous 12 months.

Despite the considerable functional impairment associated with COPD,
many patients tended to overestimate their degree of disease control
when utilizing more objective measures of assessing control. Forty-two
percent of patients who reported their disease to be completely or
well-controlled during the past year also reported experiencing daily
shortness of breath. Additionally, less than a quarter of the patients
described their disease as severe and about a third described their
disease as mild. Patients' underestimation of their disease severity and
tendency to accept their condition as the best that can be expected may
lead patients to seek less medical care and contribute to the morbidity
and mortality from this disease (ALA, February 2001**)**.

### Current Management of COPD

Smoking tobacco is the primary contributing factor in the etiology of
COPD. Smoking cessation, which has been shown to slow the rate of
decline in lung function, remains a primary objective of treatment.
However, even with the best current therapy, smoking cessation is only
successful in less than half the smokers who attempt to stop.
Additionally, for patients with more advanced COPD, prolonged smoking
results in sustained damage to the lungs with persistence of clinical
pathology and symptoms despite smoking cessation. Thus, for many
patients, pharmacological treatment for the clinical manifestations of
COPD is necessary even if they no longer smoke. Since no medication has
been shown to modify progression of COPD, pharmacological therapy has
focused on the treatment of airway obstruction, symptoms and
exacerbations associated with COPD.

Given the complex pathophysiology of the disease, it is unlikely that a
single medication can provide comprehensive control of the various
factors responsible for the clinical manifestations of COPD. Indeed,
multiple classes of medications are currently used in the treatment of
COPD, including inhaled beta~2~-agonists, anticholinergic agents,
methylxanthine preparations, and inhaled corticosteroids. Many patients
with COPD require more than one drug for optimal treatment (NHLBI/WHO
Workshop Report, 2001).

The most recently recommended approach to treatment has been presented
in evidence--based guidelines (NHLBI/WHO Workshop Report, 2001**)**
prepared as part of the Global Initiative for Chronic Obstructive Lung
Disease (GOLD). The approach recommended by the GOLD Guidelines had
extensive input from US pulmonologists.

The overall approach to managing stable COPD is characterized by a
stepwise increase in treatment depending on the severity of the disease.
Bronchodilator medications are central to the symptomatic management of
COPD (GOLD) and represent the only class of drugs with FDA approval for
the treatment of COPD. Beta~2~-agonists, anticholinergics, and
methylxanthines are bronchodilator drugs commonly used in treating COPD.
For mild disease inhaled short-acting beta~2~-agonists and
anticholinergics can be used on an as needed basis. However, with more
persistent symptoms, they may be used as maintenance therapy. These
short-acting agents need to be administered four times daily and are
frequently co-administered. Salmeterol and methylxanthines have the
advantage over short-acting bronchodilators of less frequent
administration.

For many patients, bronchodilator therapy alone does not adequately
provide relief of clinical symptoms of the disease. GOLD guidelines
recommend that regular treatment with inhaled corticosteroids (ICS) is
appropriate for symptomatic COPD patients with documented spirometric
response to ICS or in those with an FEV~1~ \<80% predicted (Stage II:
moderate COPD and Stage III: severe COPD) and repeated exacerbations
requiring antibiotics and/or oral corticosteroids.

### COPD Patients on Prescription Therapy

While inhaled corticosteroids (ICS) are not approved for the treatment
of COPD, their use is supported by current treatment practices as
assessed by using the NDC Health patient database. The NDCHealth patient
database is a collection of prescription activity captured from more
than 14,000 geographically dispersed retail pharmacies representing all
50 states. All payment types and pharmacy types are well represented in
the database, therefore, these results can be generalized to the treated
COPD population. International Classification of Diseases (ICD-9) codes
to define patient diagnosis from NDC's Value-Added Network Database were
merged with a subset of patients from the NDCHealth patient database
through the use of a unique patient identifier not provided to GSK. The
NDC's Value-Added Network ICD-9 codes are retained, up to eight
diagnoses beginning in October 2000, from the patient records provided
by the prescribing physicians through the third party processing and
reimbursement.

Patients with ICD-9 codes of chronic bronchitis, emphysema, or chronic
airways obstruction were considered to have COPD for this analysis.
Patients with a co-morbidity of asthma were specifically excluded.
Patients who had a prescription for a respiratory controller or a
relief/rescue medication for the month of July 2001, and who had a
diagnosis of COPD as defined above, were used, yielding data for
approximately 1.7 million patients.

For this analysis, ICS*,* **ADVAIR**, maintenance bronchodilators
(**SEREVENT**, **FORADIL**[^14], ipratropium, and **COMBIVENT**[^15]),
leukotriene modifiers, xanthines and cromolyns were considered
controller medications. Because scheduled albuterol cannot be
differentiated from prn use, it was not considered a controller
medication for this analysis and the concurrent use of albuterol with a
controller was not considered as combination therapy, thus **COMBIVENT**
was regarded as a single controller. However, **ADVAIR** was considered
two controllers.

A significant proportion (40%) of COPD patients was using ICS therapy
(including **ADVAIR**). Sixteen percent of patients receiving a single
controller were on an ICS alone. Forty-six percent of all COPD patients
were on combination controller therapy (2 or more controllers). The
majority of the patients on combination controller therapy (72%) were
prescribed an ICS as part of their regimen. Additionally, more than
half, (57%) were being treated with an ICS in combination with an
inhaled maintenance bronchodilator (**SEREVENT**, **FORADIL**,
ipratropium, or **COMBIVENT**). Many of these patients could therefore
benefit from the convenience of a combination product containing an ICS
and an inhaled bronchodilator. Seventeen percent of COPD patients on
combination therapy were already using **ADVAIR** as shown in the figure
below**.**

![](media/image1.wmf)COPD Patients on Prescription Therapy in July 2001

### Limitations with Available Therapy

The increasing morbidity and mortality from COPD in the US suggests
that, for many patients, currently available therapy does not meet their
needs. For some patients, limitations with current therapy may
contribute to their under-utilization of healthcare resources, including
available treatments, leading to sub-optimal control of patients'
disease. While bronchodilators represent the cornerstone of therapy in
COPD, maintenance treatment with short-acting anticholinergics and
beta~2~-agonists is problematic since they require four times-a-day
dosing and offer little treatment-effect during the latter hours of
sleep. While a more prolonged duration of action is possible during
treatment with some xanthine compounds such as sustained-release
theophylline, their gastrointestinal (GI), central nervous system (CNS)
and cardiovascular side effects may not be well tolerated by many
patients. Additionally, concerns of drug interactions with xanthines
limit their utility for patients with COPD who have considerable
comorbidities also requiring pharmacological therapy.

Due to the severity of the disease, its burden on patients and the
limited number of approved treatment options for COPD, many physicians
have had to use ICS medications off-label for its treatment without full
knowledge of their benefit/risk. This may lead to use of ICS at doses
higher than necessary and/or reliance on maintenance or frequent bursts
of systemic corticosteroids, which have considerable greater safety
risks. Considering the serious consequences associated with COPD in the
US (e.g., monetary cost, death), the availability and approval of new
medications for its treatment needs to be regarded as a medical
necessity.

Additionally, the complexity of COPD pathophysiology suggests that many
patients will require more than one class of medication to optimally
control their disease. While the use of multiple medications is likely
to improve clinical outcomes in COPD, this approach also increases
treatment complexity, which can contribute to patient confusion and
non-adherence and lead to greater morbidity. The need to simplify
medical regimens in COPD is especially critical since many patients have
significant co-morbid illnesses that also require pharmacological
therapy. The need for simpler treatment regimens in COPD was evident
during patient interviews in the *Confronting COPD in America Survey.*
More than half of the patients interviewed said that the necessity of
taking medications so often is inconvenient and that they would be more
adherent with their medication regimen if it were more convenient. A
combination product containing the two most common classes of
medications used in the treatment of COPD in a single inhaler will
simplify therapy for many patients and may improve adherence.

For many patients, difficulties using metered-dose inhalation aerosols
correctly further complicate their medical therapy and may also
contribute to poor adherence. The availability of **FLOVENT** and
**ADVAIR** in the **DISKUS** device further simplifies treatment for
these patients since it does not require co-ordination of inspiration
with actuation. The low inspiratory effort needed to obtain a dose
should further ensure that patients with even severe lung function
impairment (i.e., FEV~1~ = 20-30% predicted) successfully receive
treatment. The availability of a dose counter will remind patients when
to refill their prescription.

Thus, the availability and approval of **FLOVENT** and **ADVAIR DISKUS**
for the treatment of COPD in the US may help to address some of the
limitations with current therapy. Their availability in a
breath-actuated, easy to use delivery device may simplify COPD
management leading to improved control of the disease for many patients.
The use of these agents in the treatment of COPD is consistent with
current medical practice and supported by treatment guidelines.

### Scientific Rationale

COPD is a heterogeneous disease characterized by a predominantly
neutrophilic inflammation, tissue remodeling with inappropriate matrix
protein deposition and lung tissue destruction (Nagai & Thurlbeck, 1991)
which is thought to be secondary to the release of proteases such as
elastase from various inflammatory cells. These pathological features
are thought to be responsible for airflow obstruction and the
accelerated rate of decline of FEV~1~ in patients with COPD.

Neutrophils are the most common inflammatory cell associated with COPD
(Thompson, 1989; Lacoste, 1993; Pesci, 1998); however, it is clear that
many other inflammatory cells are also elevated and activated in the
lungs of COPD patients. These cells include lymphocytes (CD8^+^)
(Saetta, 1993 & 1999), macrophages (Saetta, 1993; Grashoff, 1997) and
eosinophils during exacerbations (Lacoste, 1993; Pesci, 1998; Zhu, 2001;
Retamales, 2001). Influx of inflammatory cells into the lung tissue is
dependent on generation of inflammatory mediators as well as
upregulation of cell adhesion molecules on the vascular endothelium.
Clinical studies have identified a wide range of mediators, which are
elevated in the lungs in COPD and could explain many of the cellular and
structural changes that are observed. Inflammatory mediators described
in the sputum or bronchoalveolar lavage fluid of COPD patients include
tumour necrosis factor α (TNFα), interleukin 8 (IL-8), Eotaxin, Rantes,
transforming growth factor β (TGFβ) and endothelin 1 (ET1). There is
also upregulation of relevant cell adhesion molecules, which allows for
the diapedeses and accumulation of inflammatory cells in the lung tissue
and airway lumen (DiStefano, 1994; Gonzalez, 1996).

In addition to inflammatory cytokines, increased levels of a range of
proteinases are also detected in COPD. These proteinases include matrix
metalloproteinases (MMPs) such as MMP-2, MMP-9 and macrophage elastase
as well as serine proteinases such as neutrophil elastase, proteinase-3
and cathepsin G. It is believed that elevation of these proteinases and
a reduction in their natural inhibitors such as tissue inhibitor of
metalloproteinase-1 (TIMP-1) is responsible for tissue destruction and
abnormal repair in the lungs of COPD and asthma patients (Finlay, 1997;
Hoshino, 1998; Ohnishi, 1998; Vignola, 1998; Shapiro, 1999,
Segura-Valdez, 2000; Cataldo, 2000). Neutrophils and neutrophil elastase
have been strongly implicated in the pathogenesis of COPD but it is now
evident that many other cells and proteinases participate in the
remodeling process that is observed in the lungs of COPD patients (Nagai
& Thurlbeck, 1991; Jeffery, 1999).

#### For the use of ICS in the treatment of COPD

Considering that inflammation is a major hallmark of COPD and
contributes to its pathophysiology and clinical manifestation, its
treatment should represent a target for pharmacological therapy.
Corticosteroids provide a broad range of anti-inflammatory effects which
also may have clinical relevance for treatment of COPD. Corticosteroids
have been shown to inhibit the *in vitro* release of IL-8 and TNFα from
macrophages (Standiford, 1992; Larsson, 1999; Ek, 1999), two key
mediators of inflammation in COPD (Keatings, 1996; Nocker, 1996).

[Studies *in vivo* have also confirmed the anti-inflammatory effects of
corticosteroid therapy in COPD. In short-term studies ICS appeared to
have no significant effect on sputum neutrophil counts (Keatings, 1997;
Culpitt, 1999; O'Brien, 2001). However, these studies were limited in
duration, patient numbers and the range of mediators and cells that had
been studied. Contradicting these findings are results from other
studies, which indicate a positive outcome on a range of inflammatory
indices with inhaled corticosteroids, including FP, in lung tissue
biopsies, bronchoalveolar lavage (BAL) and sputum from patients with
COPD. These studies are tabulated below:]{.mark}

  --------------------- -------------------------------- ----------------------
  **Study**             **Endpoint/Outcome**             **Reference**

  BDP 1.5 mg/day x 6    Improved bronchial sample cell   Thompson, 1992
  weeks                 count and epithelial lining      
                        fluid, albumin, lactoferrin and  
                        lysozyme                         

  FP 1.5 mg/day x 8     Reduced sputum neutrophil        Llewellyn-Jones,1996
  weeks                 chemotactic activity\            
                        Increased sputum anti-elastase   
                        activity                         

  BDP 1.5 mg/day x 8    Reduction in sputum neutrophils  Confalonieri, 1998
  weeks                                                  

  FP 1 mg/day x 24      Reduction in biopsy CD8+ T cells Verhoeven, 1999
  weeks                 and eosinophils                  

  FP 1 mg/day x 12      Reduction in biopsy CD8+/CD4+ T  Hattotuwa, 1999\
  weeks                 cell ratio\                      \
                        Reduction in biopsy mast cells   Hattotuwa, 2000

  BDP 1.5 mg/day x 6    Reduction in BAL neutrophils,    Balbi, 2000
  weeks                 IL8 and MPO                      

  FP 1.5 mg/day x 8     Reduction in sputum neutrophils  Yildiz, 2000
  weeks                                                  
  --------------------- -------------------------------- ----------------------

Other beneficial effects of inhaled corticosteroids may be a reduction
in plasma protein leakage and sputum volume in COPD (Schoonbrood, 1995).
In addition, it has been reported that fluticasone propionate provides
protection against bacterial and viral damage of epithelial surfaces *in
vitro* (Dowling, 1999; Man, 2001).

The study of the actions of inhaled corticosteroids on inflammatory
cells and mediators is an active field of research and many of the
actions of ICS in COPD are as yet to be described.

#### For combining a LABA and ICS in the treatment of COPD

As with asthma therapy, the combination of a long-acting beta~2~-agonist
such as salmeterol and ICS may provide better control of COPD by
treating airways obstruction and the underlying inflammation.
Salmeterol, by virtue of elevating intracellular cyclic adenosine
monophosphate (cAMP), induces a long lasting relaxation of airway smooth
muscle and a range of other cAMP-mediated physiological action that may
be of therapeutic relevance to COPD. Thus, salmeterol can reduce plasma
protein leakage (Proud, 1998), increase ciliary beat frequency
(Kanthakumar, 1994), increase mucociliary clearance (Tay, 1997;
Chambers, 1999), reduce neutrophil function (Ottonello, 1996; Bloemen,
1997), reduce neutrophil numbers in airway tissue (Jeffery, 1999), and
reduce cytokine secretion (Sekut, 1995; Oddera, 1997; Pang and Knox,
2001).

Recent *in vitro* evidence suggests that there is a mechanistic
interaction at the molecular level between ICS and beta~2~-agonists. On
the one hand, corticosteroid can up-regulate the beta~2~ receptor in the
human airways (Mak, 1995; Baraniuk, 1997) which may provide more
receptors for beta~2~-agonists to activate. On the other hand,
long-acting beta~2~-adrenoceptor agonists, can facilitate the entry of
glucocorticoid receptor/ligand complex into the nucleus and so improve
the anti-inflammatory effect of corticosteroids (Eickelberg, 1999).

Functional studies have demonstrated that such interactions can occur in
a number of cells relevant to the pathology of airway disease. Thus,
chemokine and cytokine production, including IL-8, from airway smooth
muscle cells (Pang & Knox, 2000; 2001) and monocytes (Oddera, 1998) can
be inhibited more effectively by the combination of salmeterol and
corticosteroids than by each drug alone. Furthermore, protection from
the damaging actions of *Pseudomonas aeruginosa* on the airway
epithelium can be enhanced with the combination of salmeterol and FP at
concentrations which have no effect on their own (Dowling, 1999). This
complementary action appears to be a class effect for both long-acting
beta~2~-agonists and ICS since IL1-β-induced ICAM upregulation in
fibroblasts is also more effectively inhibited by the combination of
formoterol and budesonide (Spoelstra, 1998).

This body of evidence suggests that the cooperativety between
beta~2~-agonists, particularly long-acting molecules, and ICS is a
general phenomenon observed on a number of cells relevant to the
pathology of airway disease. This data may provide a scientific
rationale to explain the improved efficacy of **ADVAIR** in COPD
compared with each component alone.

### Clinical Rationale

#### For the use of ICS in the treatment of COPD

In addition to the scientific evidence, which demonstrates the
anti-inflammatory effects of ICS on the cells and mediators associated
with COPD, findings from several clinical studies have shown that
treatment with inhaled corticosteroids improved expiratory airflow and
reduced symptoms and the rate of exacerbations associated with COPD.
While conflicting results have also been reported, efficacy of ICS in
COPD was demonstrated in the majority of the studies. Possible
explanations for studies which failed to show benefits include the
studying of a small number of patients, studying patients with mild
disease, use of a lower dose of ICS, short duration of treatment, and/or
the exclusion of patients known to be responsive to corticosteroid
and/or bronchodilator treatment. Additionally, there is evidence that
response to ICS maybe related to smoking status with patients who
continue to smoke experiencing lesser benefits then former smokers.

The table below illustrates the studies of short to medium duration (3
weeks to 1 year) and/or small sample size that demonstrated benefits
with inhaled corticosteroid therapy.

  ----------------- ------------- -------------- --------------- ------------------------
  **Short--Medium                                                
  Term Studies (3                                                
  weeks - 1 year                                                 
  Treatment                                                      
  Duration)                                                      
  Evaluating                                                     
  Symptoms\                                                      
  and Lung Function                                              
  with Positive                                                  
  Results**                                                      

  **\               **Study       **Patient      **Treatments\   **\
  Reference**       Design**      Population**   (Taken BID or   Results**
                                                 as stated)**    

  Auffarth, 1991    R, DB, PG,    24 COPD        Placebo\        Significant ↓ in dyspnea
                    PC\           patients       \               with BUD.\
                    Tx: 8 wks\    smokers or\    BUD 800mcg      No significant
                    % predicted   ex-smokers                     differences for other
                    FEV~1~:53%                                   symptoms between
                                                                 groups.\
                                                                 Pulmonary function
                                                                 changes trended in favor
                                                                 of BUD but were not
                                                                 statistically
                                                                 significant.

  Kerstjens, 1992   R, DB, PC,    39 COPD        Placebo\        At 6 months, mean FEV~1~
                    PG\           patients were  \               ↑ with BDP compared to
                    Tx: Data      evaluated at 6 Terbutaline     placebo
                    reported at   months         2000mcg/day +   
                    6 months for                 BDP 800mcg/day\ 
                    COPD\                        \               
                    % predicted                  Ipratropium     
                    FEV~1~:64%                   bromide         
                                                 160mcg/day      

  Weiner, 1995      R, DB, PC,    30 stable COPD Placebo\        BA responders showed
                    CO\           patients       \               significant improvement
                    Tx: 6wks each                BUD 400mcg      in FEV~1~ following BUD
                    treatment\                                   as compared with
                    Pre BD                                       placebo.\
                    FEV~1~:1.4L                                  BA non-responders,
                                                                 demonstrates similar
                                                                 trends but no
                                                                 significant differences.

  Thompson, 1989    R, DB, PC,    30 patients    Placebo\        BDP group showed
                    PG\           with chronic   \               significant improvement
                    Tx: 6 wks\    bronchitis,    BDP 1000mcg     in FVC, FEV~1~, and
                    % predicted   current                        FEF~25-75~. BDP
                    FEV~1~:72%    smokers                        significantly ↓ the
                                                                 bronchitis index.\
                                                                 BDP significantly
                                                                 improved parameters of
                                                                 airway inflammation.

  Dompeling, 1992   R, DB, PG\    28 COPD pts    BDP 400mcg +    Daily inhalation of BDP
                    Tx: 1 yr\     with annual    salbutamol      during one year
                    % predicted   decline of     1600mcg/day\    significantly ↓ diurnal
                    FEV~1~:70%    FEV1 ≥80mL/yr  \               variation of peakflow,
                                  and ≥1 EX/yr   BDP 400mcg +    and ↓ symptoms when
                                  following      ipratropium     added to bronchodilator
                                  first 2 yr of  bromide         treatment in COPD
                                  treatment with 160mcg/day      subjects.
                                  only BD                        
                                  (salbutamol or                 
                                  ipratropium                    
                                  bromide)                       

  Paggiaro, 1998    R, DB, PG\    281 COPD       Placebo\        Change in FEV~1~ with FP
                    Tx: 6 months\ patients       \               was significantly ↑
                    %predicted                   FP 500mcg       compared with placebo.\
                    FEV~1~:57%                                   An ↑ in FEV~1~ was
                                                                 observed in the FP
                                                                 group, while the placebo
                                                                 group showed a ↓.\
                                                                 Bronchitic symptoms
                                                                 significantly improved
                                                                 with FP. More
                                                                 moderate/severe
                                                                 exacerbations in PLA vs.
                                                                 FP

  R = randomized;                                                
  DB = double                                                    
  blind; OL = open                                               
  label; PG =                                                    
  parallel group;                                                
  CO = cross over;                                               
  PC = placebo                                                   
  controlled\                                                    
  Tx = treatment                                                 
  duration; EX =                                                 
  exacerbation; BDP                                              
  = beclomethasone                                               
  dipropionate; BUD                                              
  = budesonide;\                                                 
  BA =                                                           
  beta-agonist; TAA                                              
  = triamcinolone                                                
  acetonide; FP =                                                
  fluticasone                                                    
  propionate; BD =                                               
  bronchodilator;                                                
  PLA = placebo                                                  
  ----------------- ------------- -------------- --------------- ------------------------

Of the short-medium term studies, treatment with FP was evaluated in one
6-month study and was shown to be beneficial in the treatment of COPD
**(**Paggiaro, 1998). Patients (n=142) treated for 6 months with FP MDI
440mcg BID (equivalent to 500mcg BID from **DISKUS**) demonstrated
increased FEV~1~ of 90mL and a reduction of cough and sputum production.
In contrast, with 6 months of placebo treatment (n=139), FEV~1~
decreased by 70mL and the prevalence of cough and sputum production was
unchanged. A statistically significant difference between FP and placebo
was observed for change in FEV~1~, symptom prevalence, and moderate and
severe exacerbations.

The table below illustrates the studies of short to medium duration (3
weeks to 1 year) and/or small sample size that did not demonstrate
benefits with inhaled corticosteroid therapy.

  ------------------- ------------- -------------- --------------- ----------------------
  **Short--Medium                                                  
  Term Studies (3                                                  
  weeks -- 6 months                                                
  Treatment Duration                                               
  ) Evaluating                                                     
  Symptoms and Lung                                                
  Function with                                                    
  Negative Results**                                               

  **\                 **Study       **Patient      **Treatments\   **\
  Reference**         Design**      Population**   (Taken BID)**   Results**

  Engel, 1989         R, DB, PC,    18 chronic     Placebo\        No difference in
                      PG\           bronchitis     BUD 400mcg      pulmonary function or
                      Tx: 12 wks\   pts, all                       most symptoms
                      % predicted   current                        measured.
                      FEV~1~:97%    smokers                        

  Watson, 1992        DB, PC, CO\   14 male        Placebo\        No difference in
                      Tx: 12 wk     smokers with   BUD 600mcg      pulmonary function or
                      treatment     measurable BHR                 most symptoms
                      periods\      to inhaled                     measured.
                      % predicted   histamine                      
                      FEV~1~:80%                                   

  Keatings, 1997      PC, SB, CO\   13 pts, with   Placebo\        No difference in
                      Tx: 2 wk      stable COPD,   BUD 800mg       pulmonary function or
                      treatment     current or                     markers of
                      periods\      former smokers                 inflammation.
                      % predicted                                  
                      FEV~1~:35%                                   

  Bourbeau, 1998      R, DB, PC,    79 COPD pts,   Placebo\        No difference in
                      PG\           current or     BUD 800mcg      pulmonary function or
                      Tx: 6 mos\    ex-smokers                     symptoms measured.
                      % predicted   that showed no                 
                      FEV~1~:36%    response to BA                 
                                    or OCS                         

  R = randomized; DB                                               
  = double blind; SB                                               
  = single blind; PG                                               
  = parallel group;                                                
  CO = cross over; PC                                              
  = placebo                                                        
  controlled; Tx =                                                 
  treatment duration;                                              
  BA = beta-agonist;                                               
  BUD = budesonide;                                                
  OCS = oral                                                       
  corticosteroids;\                                                
  PLA = placebo                                                    
  ------------------- ------------- -------------- --------------- ----------------------

Four large-scale, placebo-controlled, randomized, double-blind 3-year
trials of the treatment of COPD with inhaled corticosteroids found no
effect on the rate of decline of FEV~1~, the primary endpoint in these
studies. However in three of the four trials, other indications of
efficacy were observed. The table below summarizes the findings of these
studies.

  ------------------- ------------ -------------- -------------- -----------------------
  **Long-Term (3 year                                            
  Treatment Duration)                                            
  Studies**                                                      

  **\                 **Study      **Patient      **Treatments   **\
  Reference**         Design**     Population**   (Taken BID)**  Results**

  Burge, 2000\        R, DB, PC,   751 current or Placebo\       FP ↑ mean FEV~1~ but
  ISOLDE Trial        PG\          former smokers \              did not significantly
                      Tx: 3 yrs\   with COPD      FP 500mcg      alter rate of decline.\
                      % predicted                                FP ↓ median
                      FEV~1~: 50%                                exacerbation rate by
                                                                 25%.\
                                                                 FP produced a slower
                                                                 decline in health
                                                                 status.\
                                                                 FP had fewer fractures
                                                                 (9, 2%) than PLA (17,
                                                                 5%).

  Lung Health II      R, PC, DB,   1116 mostly    Placebo\       TAA did not
  Study, 2000         PG\          current        \              significantly ↓ rate of
                      Tx: 3 yrs.\  smokers with   TAA 600mcg     decline of pulmonary
                      % predicted  COPD                          function.\
                      FEV~1~: 64%                                TAA group had fewer
                                                                 respiratory symptoms.\
                                                                 TAA group had fewer
                                                                 visits to MD due to
                                                                 respiratory illness.\
                                                                 TAA group had lower
                                                                 airway reactivity in
                                                                 response to
                                                                 methacholine
                                                                 challenge.\
                                                                 TAA group had
                                                                 significantly greater
                                                                 changes in BMD of
                                                                 lumbar spine and
                                                                 femoral neck compared
                                                                 to placebo.

  Vestbo, 1996\       R, DB, PC,   290 COPD pts   Placebo\       BUD did not alter rate
  COPEHAGEN City      PG\          unresponsive   BUD 400mcg     of decline in FEV~1.~
  Study               Tx: 3yrs\    to BA or OCS.\                
                      % predicted  75% current                   
                      FEV~1~: 87%  smokers                       

  Pauwels, 1999\      R, DB, PC,   1277 mild COPD Placebo\       BUD ↑ mean FEV~1~ but
  EUROSCOP            PG\          pts, all       \              did not significantly
                      Tx: 3 yrs\   current        BUD 400mcg     alter rate of decline.\
                      % predicted  smokers                       No difference in BMD
                      FEV~1~: 76%                                except significant
                                                                 difference at
                                                                 trochanter in favor of
                                                                 BUD.

  R = randomized; DB                                             
  = double blind; PG                                             
  = parallel group;                                              
  PC = placebo                                                   
  controlled; Tx =                                               
  treatment                                                      
  duration;\                                                     
  BDP =                                                          
  beclomethasone                                                 
  dipropionate; BUD =                                            
  budesonide; BA =                                               
  beta-agonist; OCS =                                            
  oral                                                           
  corticosteroids;\                                              
  TAA = triamcinolone                                            
  acetonide; FP =                                                
  fluticasone                                                    
  propionate; BD =                                               
  bronchodilator; PLA                                            
  = placebo                                                      
  ------------------- ------------ -------------- -------------- -----------------------

Other evidence for the benefit of inhaled corticosteroid therapy in COPD
can be seen in the setting of treatment withdrawal. Two recently
published trials have shown a deterioration of lung-function and
increasing symptoms or exacerbations when maintenance inhaled
corticosteroid therapy was withdrawn (O'Brien, 2001; Jarad, 1999).
Additionally, patients treated with inhaled corticosteroids
post-discharge from hospitalization for COPD had 24% fewer repeat
hospitalizations (RR= 0.76) and a 29% reduction in mortality (RR=0.71)
compared with patients not treated with inhaled corticosteroids
post-discharge (Sin & Tu, 2001).

The overall findings from these trials indicate that inhaled
corticosteroids, including FP are beneficial in the treatment of COPD.
While ICS therapy may not reduce the rate of lung function decline in
patients with COPD, their use has been shown to improve lung function
and reduce symptoms and exacerbations which are responsible for
substantial morbidity in this disease. These findings support the
widespread use of ICS in the treatment of COPD by US physicians.
Considering the importance of inflammation in the pathophysiology of
COPD and lack of more specific anti-inflammatory therapy with proven
clinical benefit, the availability and use of ICS in COPD provides an
important treatment option for patients.

#### For the use of a LABA and ICS together in the treatment of COPD

Due to the complex pathophysiology of COPD, no single medication is
likely to provide optimal control of the clinical manifestations of the
disease. Inhaled long-acting beta~2~-agonists (LABA) and inhaled
corticosteroids treat different aspects of this pathophysiology and
hence will provide complementary benefits in the treatment of COPD.
Current clinical practice and treatment guidelines support the
concomitant use of these two classes of drugs in the management of COPD.

Unlike in asthma where the combination of an inhaled corticosteroid and
a long-acting beta~2~-agonist has been extensively studied, limited
clinical trial data is available on the use of these two classes of
drugs concurrently in the treatment of COPD. Only one previous study
(Cazzola, 2000) has examined the treatment of COPD with a combination of
a LABA (salmeterol) and an ICS (FP) administered by separate delivery
devices. Patients with moderate to severe COPD (Mean FEV~1~ ≈ 1.2L) were
treated for 3 months with salmeterol 50mcg BID (N=17) or salmeterol
50mcg BID together with titrated theophylline (N=16), FP 250mcg BID
(N=18) or FP 500mcg BID (N=18). All treatments resulted in gradually
increasing pre-dose FEV~1~ as a function of time. At 3 months the only
apparent difference from salmeterol 50mcg in the magnitude of increased
FEV~1~ (163mL) was for treatment with salmeterol + FP 500mcg (239mL).
This difference was not statistically significant because of the small
number of subjects. These findings suggest that it may be beneficial to
combine an inhaled long-acting beta~2~-agonist with an inhaled
corticosteroid for the treatment of COPD.

### Summary of Rationale

The rationale for the development of **FLOVENT** and **ADVAIR DISKUS**
for the treatment of COPD was based on sound scientific and clinical
grounds and can be summarized as follows:

-   COPD is defined by the American Thoracic Society as 'a disease state
    characterized by the presence of airflow obstruction due to chronic
    bronchitis or emphysema; the airflow obstruction is generally
    progressive, may be accompanied by airway hyperreactivity, and may
    be partially reversible.'

-   Emphysema and chronic bronchitis are complex pathophysiological
    conditions and frequently co-exist in the same patient. While
    neutrophilic inflammation is characteristic of the disease, a
    multitude of cells, mediators, and tissues have been implicated in
    its pathogenesis and contribute to its clinical severity.

-   COPD is a disease that exacts considerable toll on patients and
    society. It is currently the fourth leading cause of mortality in
    the US and projected to be the third by 2020. Morbidity from COPD
    also is rising with an estimated 668,363 hospital discharges in 1998
    and estimated annual cost to the nation in 2000 of 30.4 billion
    dollars.

-   The *Confronting COPD in America Survey* revealed that many patients
    with COPD experience substantial dyspnea, which impacts their
    activities of daily living and use of health care resources. About
    50% of patients reported that COPD limited their ability to work,
    sleep, perform household chores, or participate in social
    activities. Forty-five percent of patients required emergency care
    and 14% required hospitalization for their disease within the past
    year.

-   While smoking cessation is a primary objective of therapy,
    pharmacological therapy to alleviate airway obstruction, symptoms,
    and exacerbations is necessary for many patients even if they no
    longer smoke.

-   No medication has shown to modify disease progression in COPD, hence
    current approach to treatment advocated by guidelines consists of
    bronchodilator medications and ICS depending on disease severity.

-   Given the complexity of the disease, many patients require multiple
    medications to control the various pathophysiological processes
    responsible for the clinical manifestations of COPD.

-   While bronchodilators are the only agents currently approved by the
    FDA for COPD treatment in the US, considerable off-label use of ICS
    alone or with maintenance bronchodilators is occurring. Examination
    of prescription activity in the US indicates that approximately 40%
    of COPD patients are currently receiving ICS therapy. Additionally,
    46% of patients with COPD are currently receiving combination of two
    or more drugs of which 72% are prescribed an ICS as part of their
    regimen. Fifty-seven percent of these patients are being treated
    with maintenance bronchodilators and ICS.

-   Despite the availability of medications and guidelines advocating
    their appropriate use in the management of COPD, the control of COPD
    in the US remains sub-optimal.

-   For many patients, limitations such as convenience, tolerability,
    and effectiveness with current therapy may contribute to its under
    utilization leading to sub-optimal control of their disease.

-   Due to limited approved treatment options, many physicians have had
    to use ICS off-label without full knowledge of their benefit/risk.
    This may lead to patients receiving higher doses than necessary
    and/or reliance on frequent oral corticosteroid bursts with greater
    safety risks.

-   While many patients require treatment with multiple medications to
    improve clinical outcomes in COPD, this approach also increases
    treatment complexity contributing to patient confusion and
    non-adherence and may lead to greater morbidity.

-   Considering the serious public health consequences associated with
    COPD in the US, the availability and approval of new medications for
    its treatment should be regarded as a medical necessity.

-   Considerable scientific evidence supports the anti-inflammatory
    effects of ICS in the pathophysiology of COPD. Results from seven
    recent studies have demonstrated that ICS therapy in COPD is
    associated with reduction in airway inflammation (including
    neutrophils and CD8^+^ T-cells) as determined by lung biopsies,
    bronchoalveolar lavage, and sputum.

-   The administration of inhaled long-acting beta~2~-agonists and
    inhaled corticosteroids together provides broader as well as greater
    effects on cells, mediators, and tissues contributing to the
    pathophysiology of COPD than that achievable with either agent alone
    and provides a rationale for the clinical benefit of administering
    these two agents together.

-   The majority of clinical evidence indicates that inhaled
    corticosteroids including fluticasone propionate are beneficial in
    the treatment of COPD. While ICS therapy may not reduce the rate of
    lung function decline in patients with COPD, their use has been
    shown to improve lung function and reduce symptoms and exacerbations
    which are responsible for substantial morbidity in this disease.
    These findings support the widespread use of ICS in the treatment of
    COPD by US physicians and recommendations for their use in COPD
    treatment guidelines.

-   While clinical trial data examining concurrent therapy with inhaled
    long-acting beta~2~-agonists and corticosteroids together in the
    treatment of COPD are limited, results from a recent trial indicate
    that the addition of fluticasone propionate to salmeterol was
    associated with greater benefit than use of salmeterol alone.

-   The availability and approval of **FLOVENT** and **ADVAIR**
    **DISKUS** in the US will help physicians to make informed decisions
    regarding their use in the management of COPD and will help to
    address some of the limitations with current therapy. Its
    availability in a breath-actuated, easy to use delivery device may
    simplify COPD management leading to improved control of COPD for
    many patients.

## Regulatory

### Proposed Indications and Dosage and Administration

Clinical trials described in this document support the indications
listed below for both **FLOVENT DISKUS** and **ADVAIR DISKUS**. The
strength intended for market of the COPD indication for **FLOVENT
DISKUS** is fluticasone propionate 250mcg/blister. The strengths
intended for market of the COPD indication for **ADVAIR DISKUS** are
fluticasone propionate 250mcg and salmeterol 50mcg/blister (250/50) and
fluticasone propionate 500mcg and salmeterol 50mcg/blister (500/50).

# FLOVENT DISKUS {#flovent-diskus-1 .NoNum:Head5}

**FLOVENT DISKUS** is indicated for the long-term, twice-daily
maintenance treatment of COPD (including emphysema and chronic
bronchitis).

The starting dosage for adults is 1 inhalation (250mcg) twice daily. For
patients who do not respond adequately to the starting dose, increasing
the dose to 500mcg twice daily may provide additional control.

# ADVAIR DISKUS {#advair-diskus-1 .NoNum:Head5}

**ADVAIR DISKUS** is indicated for the long-term, twice-daily
maintenance treatment of COPD (including emphysema and chronic
bronchitis).

The starting dosage for adults is 1 inhalation (250/50) twice daily
(morning and evening, approximately 12 hours apart). For patients who do
not respond adequately to the starting dose, replacing the
250/50-strength with the 500/50-strength may provide additional control.

### Summary of Significant FDA Interactions During the Clinical Development Program

A meeting was held with the FDA on April 21, 1998 to discuss the
clinical program for investigating the effectiveness and safety of
salmeterol, fluticasone propionate, and the combination of salmeterol
and fluticasone propionate via the **DISKUS** for the treatment of COPD,
including emphysema and chronic bronchitis. The following key agreements
were reached:

-   The clinical trials, as described, are acceptable provided the FDA
    "combination policy" is met for the combination product (i.e., the
    contribution of both components in the combination are
    demonstrated).

-   Replication of concept only is required for the two doses of the
    combination product.

-   GlaxoSmithKline (GSK) will monitor 12-hour serial FEV~1~ in a subset
    of patients in one clinical study to confirm the 12-hour duration of
    action of salmeterol.

-   Describe the fluticasone propionate systemic exposure and effect on
    serum cortisol in a subset of COPD subjects in one study (FLTA3025).

-   GSK will compare the safety database from the **FLOVENT** asthma NDA
    to the COPD population and also compare fluticasone propionate
    systemic exposure and effect on serum cortisol in the two
    populations.

-   The use of a revised Chronic Bronchitis Symptom Questionnaire (CBSQ)
    is acceptable provided validation data are submitted.

-   The use of the Chronic Respiratory Disease Questionnaire (CRDQ) to
    assess quality of life is acceptable provided the same type of
    assumptions/analyses are defined a priori and used as in the
    **SEREVENT** MDI COPD program.

### Non-US Marketing History

#### Fluticasone Propionate

In markets outside the US, approval has been obtained for fluticasone
propionate for COPD in the following countries as of May 31, 2001:

  ------------- ------------- ------------- ------------- ------------- --------------
  **Country**   **Approval    **Country**   **Approval    **Country**   **Approval
                Date**                      Date**                      Date**

  Argentina     01-Dec-2000   Ghana         04-Apr-2001   Panama        21-Oct-1999

  Aruba         04-Apr-2001   Grenada       04-Apr-2001   Paraguay      04-Nov-1999

  Austria       24-Nov-1997   Guatemala     21-Oct-1999   Peru          Aug-1999

  Bahamas       04-Apr-2001   Guyana        04-Apr-2001   Philippines   25-Mar-2000

  Bangladesh    30-Dec-1999   Haiti         04-Apr-2001   Romania       17-Sep-1999

  Barbados      04-Apr-2001   Holland       21-Apr-2000   Russia        24-Mar-1999

  Belgium       03-Jul-2000   Honduras      21-Oct-1999   Slovakia      30-Mar-2001

  Belize        04-Apr-2001   Iceland       \*            South Africa  31-May-2000

  Bermuda       04-Apr-2001   Ireland       18-Oct-1996   Spain         06-Nov-2000

  Bolivia       04-Apr-2001   Israel        11-May-2000   Suriname      04-Apr-2001

  Botswana      04-Apr-2001   Jamaica       22-Jul-1999   Taiwan        28-Aug-2001

  Bulgaria      31-Mar-2001   Kenya         04-Apr-2001   Tanzania      04-Apr-2001

  Cambodia      05-Apr-2001   Latvia        16-Jun-1999   Thailand      29-Apr-2001

  Chile         28-Sep-2000   Lithuania     11-Sep-2000   Trinidad &    22-Jul-1999
                                                          Tobago        

  Columbia      10-Jul-2000   Luxembourg    30-Mar-2000   Turkey        31-May-2000

  Congo         04-Apr-2001   Malawi        04-Apr-2001   Uganda        04-Apr-2001

  Costa Rica    21-Oct-1999   Malta         04-Apr-2001   Uruguay       16-Aug-2000

  Cuba          04-Apr-2001   Mauritius     04-Apr-2001   Venezuela     17-Jun-2000

  Czech         20-Sep-2000   Mexico        27-Jul-1999   Yugoslavia    01-Dec-1999
  Republic                                                (Serbia)      

  Dominican     21-Oct-1999   Myanmar       05-Apr-2001   Zambia        04-Apr-2001
  Republic                                                              

  Ecuador       31-Mar-2000   Netherlands   22-Jul-1999   Zimbabwe      04-Apr-2001
                              Antilles                                  

  El Salvador   21-Oct-1999   Nicaragua     21-Oct-1999                 

  Germany       23-Sep-1999   Pakistan      30-Jul-1999                 

  \*Approved                                                            
  with original                                                         
  asthma                                                                
  application                                                           
  ------------- ------------- ------------- ------------- ------------- --------------

#### Salmeterol/Fluticasone Propionate Combination

The salmeterol/fluticasone propionate combination product has not
received approval for COPD in any country. As of October 1, 2001
applications for COPD are pending in Canada (submitted April 30, 2001)
and Europe (submitted September 28, 2001).

### Withdrawals/Rejections

The applications for fluticasone propionate submitted to foreign
regulatory authorities were based on different clinical studies than
those supporting the current submission. Thus, the reasons for
withdrawal or rejection may not be relevant to this application.

Applications for fluticasone propionate for COPD have been withdrawn by
GSK or rejected by regulatory authorities in the following countries:
Australia, Canada, Denmark, Estonia, Finland, Italy, New Zealand,
Norway, Switzerland and the United Kingdom. The most common reason for
withdrawal or rejection was inadequate efficacy to support the COPD
indication. No applications have been withdrawn or rejected due to
safety concerns.

No applications for the salmeterol/fluticasone propionate combination
product have been withdrawn by GSK or rejected by any regulatory
authority.

# CLINICAL PHARMACOLOGY AND BIOAVAILABLITY

## Program Objectives

The Clinical Pharmacology program for this submission builds upon the
body of knowledge generated from past submissions, especially for
**ADVAIR DISKUS** (NDA 21-077) for the treatment of asthma. In the prior
submission FP and SAL systemic exposure from **ADVAIR DISKUS** in
healthy volunteers and subjects with asthma was shown to be similar to
the individual inhalers resulting in similar pharmacodynamic effects.

The primary aim of the current program was to characterize FP
pharmacokinetics and pharmacodynamics in subjects with COPD and compare
these data to the available data for patients with asthma. The
pharmacokinetics and pharmacodynamics of FP in subjects with COPD were
examined in studies FLTA3025 and FMS40243.

## Study FLTA3025

The study was a randomized, double-blind, parallel-group,
placebo-controlled, multicenter trial to compare the efficacy and safety
of FP 250mcg and 500mcg twice daily using the 250mcg and 500mcg
**DISKUS** strengths in subjects with COPD. After at least 4 weeks of
dosing, 7 blood samples were obtained after the morning dose over a
12‑hour interval from a sub-population of 86 subjects for measurements
of plasma FP and serum cortisol.

A dose-related increase in the extent of systemic exposure was observed.
Mean FP AUC~last~ following 500mcg twice daily (539.0pg\*h/mL) was 74%
greater than after 250mcg twice daily (310.6pg\*h/mL). Mean C~max~
following 500mcg (83.6pg/mL) was 58% greater than after 250mcg
(52.9pg/mL). The rate of absorption into the systemic circulation was
similar after each dose. Median t~max~ values were 1.1h after 250mcg and
1.0h after 500mcg.

Estimates of the terminal elimination half-life were limited in many
subjects because either a log-linear phase could not be identified or
could only be estimated by three points. In those subjects where an
estimate was made, t~1/2~ averaged 7.6h, which is consistent with
previous findings (Brutsche, 2000; Mackie, 2000; Mackie, 1996).

Mean serum cortisol AUC~12~ values following the 250mcg and 500mcg
treatments were 10% and 21% lower than placebo, respectively. The
difference reached statistical significance for the 500mcg dose, but not
for the 250mcg dose. However, neither difference is considered to be
clinically significant (Dluhy, 1998; Wilson, 1998) and the difference
between the two active treatments was not significant. Mean cortisol
C~min~ for placebo (123pmol/mL) and the 250mcg treatment (117pmol/mL)
were similar and different from the 500mcg treatment (85pmol/mL). The
lower limit of the 95% confidence interval for C~min~ for the 500mcg
treatment (68.1pmol/mL) was within the normal range (Burtis & Ashwiid,
1999).

## Study FMS40243 

This study was a randomized, double blind, double-dummy, 2-way crossover
design. Thirteen healthy subjects and 10 subjects with COPD were
enrolled. Subjects were randomized to receive each of the following
treatments:

-   inhaled FP 500mcg twice daily from a HFA MDI with a spacer for
    7 days followed by a single inhaled dose of FP 1000mcg and a placebo
    infusion, and

-   inhaled beclomethasone dipropionate 1000mcg twice daily from a CFC
    MDI with a spacer for 7 days followed by a single dose of inhaled
    placebo and FP 1000mcg intravenous infusion.

The pharmacokinetics and pharmacodynamic effects of FP were assessed
from serial plasma FP concentrations and serial serum cortisol
concentrations measured over a 12 hour dosing interval after the 1000mcg
FP inhaled and intravenous doses. Urinary cortisol excretion was
measured over 24 hours before the start of the inhaled dosing run-in and
over the 24 hours prior to the last inhaled or intravenous dose.

Systemic exposure in COPD subjects following inhalation was 35% less
than the systemic exposure observed in healthy subjects. Peak
concentrations in COPD subjects were 44% less than the concentrations
observed in healthy subjects and occurred at 0.75h in both populations.
Systemic exposure following intravenous administration was similar in
both populations. Absolute bioavailability following inhaled
administration in COPD subjects (13.3%, 95% CI: 8.96 -- 19.83) was
considerably lower compared to healthy subjects (21.2%, 95% CI: 13.4 --
33.0) (Singh, 2001) and similar to subjects with asthma (10%) (Brutsche,
2000).

The lower systemic exposure observed resulted in significantly less
effect on serum cortisol, which was 83% higher in COPD subjects compared
to healthy subjects.

## FP Systemic Exposure

Systemic exposure data from 67 COPD subjects in FLTA3025 and FMS40243
were compared with data from 103 asthma subjects from 5 studies
(FLTA3001, FLD230, FLTA2001, SFCB3019, FAS40022). Data were obtained
following multiple dosing and corrected for differences in dose and
assay (Daley-Yates, 2000; Falcoz, 2000). While it was not appropriate to
perform statistical comparisons on the data because the populations were
not matched for differences in demographics and pulmonary function,
graphical comparisons and summary statistics of individual data were
made. The range of systemic exposure observed in the COPD population was
within the range observed in subjects with asthma.

  -----------------------------------------------------------------------
  ![](media/image2.wmf)

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While subject numbers using the marketed MDI were limited, higher
exposure following the MDI was observed when the AUC data were not
corrected for device. The median and range with the MDI in asthma
subjects was 950pg\*h/mL (0 -- 2448pg\*h/mL) compared to 619pg\*h/mL
(79 - 1690pg\*h/mL) with the **DISKUS** in COPD subjects. Thus, the
extensive safety data generated in asthma subjects can be used to
support the safety in subjects with COPD. Bone mineral density results
from the MDI study (FLTA3001) are described in Section 7.

## Serum Cortisol

A comparison of the effects of FP systemic exposure on serum cortisol
can be compared using data from two asthma studies (FLTA2001 and
SFCB3019) and one COPD study (FLTA3025). While blood-sampling regimens
differed slightly, the same dose of FP from the **DISKUS** device was
used in each study. Cortisol measurements were made after four weeks
(FLTA2001 and FLTA3025) and 12 weeks (SFCB3019) of treatment.

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  height="4.589583333333334in"}

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The range of serum cortisol values following drug administration was
similar in COPD subjects and asthmatics and was generally comparable to
placebo subjects in FLTA2001 and FLTA3025.

## Relationship Between FP Systemic Exposure and Serum Cortisol

Earlier work in healthy subjects demonstrated a relationship between
increases in FP systemic exposure and decreases in cortisol (Mackie &
Bye, 2000). This relationship was examined using the asthma and COPD
subjects in FLTA2001, SFCB3019, and FLTA3025. The relationship between
FP systemic exposure and serum cortisol levels in asthma and COPD
subjects were similar and differences from placebo were minimal due to
low FP systemic exposure following the 500mcg dose. Most values were
well within the range observed for placebo subjects.

## Clinical Pharmacology Conclusions

The clinical pharmacology program conducted in support of the use of
Flovent and Advair Diskus in the treatment of COPD build on the
information obtained as part of the development program for asthma.
Studies in healthy volunteers and patients with asthma had shown that
the pharmacokinetics and pharmacodynamic effects of administering
fluticasone propionate and salmeterol as a combination product were
comparable to that when these agents were administered alone. The
primary aim of the current program was to characterize FP
pharmacokinetics and pharmacodynamics in patients with COPD and to
compare these data to the available data for patients with asthma.

-   A dose-related increase in FP systemic exposure was observed in COPD
    subjects following an increase in dose from 250mcg to 500mcg twice
    daily with C~max~ averaging 53pg/mL and 84pg/mL, respectively.

-   No statistically significant reduction (10%) in serum cortisol was
    observed with FP 250mcg compared with placebo treatment in subjects
    with COPD. There was a small, statistically significant reduction
    (21%) in serum cortisol with FP 500mcg compared to placebo; however,
    this difference is not considered to be clinically significant.

-   Systemic exposure following inhaled administration of FP in COPD
    subjects was considerably lower compared to healthy subjects and
    similar to asthma subjects.

-   Systemic exposure following inhaled administration of FP with the
    **DISKUS** was considerably lower than the currently marketed CFC
    MDI.

-   The range of systemic exposure to FP in the COPD population was
    within the range observed in subjects with asthma. The range of
    serum cortisol values following drug administration was similar in
    COPD subjects and asthmatics and was generally comparable to placebo
    subjects.

-   These findings allow the extrapolation of the long-term safety data
    in asthma to patients with COPD.

# DESIGN OF PIVOTAL STUDIES 

## Introduction

A major objective of the clinical development program was to show
superior efficacy and comparable safety of **ADVAIR DISKUS** (FSC)
compared to the individual components administered at the same doses in
patients with COPD. An additional objective of the clinical program was
to demonstrate the overall efficacy versus safety of **FLOVENT**, (FP),
**SEREVENT** (SAL), and **ADVAIR DISKUS** versus placebo (PLA) in the
treatment of COPD. A total of three studies in patients with COPD were
performed in support of these objectives. Details on these studies are
shown in the table below. All study medication was administered twice
daily.

  -------------- ------------- -------------- ------ ------------- ------------ ---------------
  **\            **\           **Treatment\   **\    **Duration\   **Baseline   **\
  Study**        Objective**   (mcg BID)**    N**    (weeks)**     FEV~1~ (%    Primary
                                                                   pred)**      Efficacy**

  **FLTA3025**   Superiority   FP 250\        216\   24            41.0%\       Change from
                 of FP over    FP 500\        218\                 39.8%\       baseline at
                 placebo       PLA            206                  41.3%        endpoint in AM
                                                                                pre-dose FEV~1~

  **SFCA3006**   Superiority   FSC 500/50\    165\   24            40.9%\       Change from
                 of            FP 500\        168\                 41.4%\       baseline at
                 combination   SAL 50\        160\                 40.3%\       endpoint in AM
                 over FP &     PLA            181                  41.5%        pre-dose
                 SAL\                                                           FEV~1~\
                 \                                                              \
                 Superiority                                                    Change from
                 of\                                                            baseline at
                 FP & SAL over                                                  endpoint in 2h
                 placebo                                                        post\--dose
                                                                                FEV~1~

  **SFCA3007**   Superiority   FSC 250/50\    178\   24            41.4%\       Change from
                 of            FP 250\        183\                 42.0%\       baseline at
                 combination   SAL 50\        177\                 41.9%\       endpoint in AM
                 over FP &     PLA            185                  42.1%        pre-dose FEV~1\
                 SAL\                                                           ~\
                 \                                                              Change from
                 Superiority                                                    baseline at
                 of\                                                            endpoint in 2h
                 FP & SAL over                                                  post\--dose
                 placebo                                                        FEV~1~
  -------------- ------------- -------------- ------ ------------- ------------ ---------------

## Study Design

Each of the three studies (SFCA3006, SFCA3007, and FLTA3025) were
randomized, double-blind, parallel-group, placebo-controlled,
multi-center trials designed and conducted in an identical manner.

Entry requirements were identical in the three studies. Subjects had to
meet the ATS definition of COPD (ATS, 1987), be at least 40 years of
age, have a current or prior history of ≥20-pack years of cigarette
smoking, and have a history of cough productive of sputum on most days
for at least 3 months of the year, for at least 2 years, that was not
attributable to another disease process. Subjects were required to have
a baseline FEV~1~ \<65% of predicted normal, but \>0.70L or FEV~1~
≤0.70L and \>40% of predicted normal with an FEV~1~/FVC ratio of ≤70%.
Subjects also had to achieve a score of ≥2 (moderate dyspnea) on the
Modified Medical Research Council (MMRC) Dyspnea Scale (ATS News, 1982)
at Screening and have minimal symptoms of chronic bronchitis (morning
cough and sputum) at Baseline.

Specific exclusion criteria were current diagnosis of asthma, current
use of oral or high-dose inhaled corticosteroids, abnormal clinically
significant ECG, need for long-term oxygen therapy, moderate or severe
exacerbation during the run-in, and any significant medical disorder
that would place the subject at risk, interfere with the evaluations, or
influence study participation.

Subjects who met the entrance criteria began a 2-week, single-blind,
run-in period with placebo treatment. All concurrent inhaled or oral
sympathomimetic or anticholinergic bronchodilators and inhaled or
intranasal corticosteroids were discontinued at the Screening Visit.
Concurrent theophylline therapy could be continued if a stable regimen
was maintained for 1 month prior to study entry and for the duration of
the study. Adjustments could be made to maintain a therapeutic dose of
theophylline during the study.

All subjects received **VENTOLIN** Inhalation Aerosol or nebules to use
as needed for the duration of the trial, including the 2-week run-in
period.

Subjects who successfully completed the run-in period were assigned to
one double-blind treatment via the **DISKUS** BID for 24 weeks. Subjects
were evaluated weekly for the first 4 weeks of treatment (Weeks 1, 2, 3,
and 4), every 2 weeks until Week 8 (Weeks 6 and 8), and then at 4-week
intervals for the remainder of the study (Weeks 12, 16, 20, and 24).

Subjects could be discontinued from the study for AEs, lack of efficacy,
use of corticosteroids or other prohibited medication, initiation of
continuous positive airway pressure (CPAP), withdrawal of consent, or
resumption of smoking or quitting smoking.

## Efficacy Measures

### Primary Efficacy Measure

FEV~1~ was chosen as the primary efficacy measure due to its wide
acceptance as a reproducible and objective indicator of disease severity
and prognosis in COPD (ATS 1991; Crapo 1981; Kanner 1996). However,
because beta-agonists and corticosteroids treat different aspects of the
disease, two different FEV~1~ measures were assessed: pre-dose FEV~1~
for FSC and for FP, and 2-hour post dose FEV~1~ for FSC and for SAL. The
primary analyses were those performed at Endpoint comparing the primary
measures specified above between treatment groups. The Endpoint was
defined as the final evaluable measurement for the subject.

**Pre-dose FEV~1.~** Differences between pre-dose FEV~1~ on the first
day of treatment and pre-dose FEV~1~ at subsequent treatment visits were
used to compare:

FSC 250/50 and FSC 500/50 with SAL (in order to assess the contribution
of FP to FSC)

FSC 250/50 and FSC 500/50 with PLA

FP 250 and FP 500 with PLA

**2-Hour Post-Dose FEV~1~.** Baseline was defined as pre-dose FEV~1~ on
the first day of treatment (Day 1). Change from Baseline in 2-hour
post-dose FEV~1~ and all subsequent treatment visits were used to
compare:

FSC 250/50 and FSC 500/50 with the corresponding strength of FP, FP 250
or FP 500 (in order to assess the contribution of SAL to FSC)

FSC 250/50 and FSC 500/50 with PLA

SAL 50 with PLA

### Key Secondary Efficacy Measures

#### Baseline/Transition Dyspnea Index (BDI/TDI)

The BDI/TDI (Mahler, 1984) was used to assess the effect of treatment on
relief of dyspnea. This BDI/TDI scale was developed to provide a
clinical measurement of dyspnea. The Baseline (BDI) scale administered
on Treatment Day 1 rated the Baseline severity of dyspnea. Severity was
rated on a graded scale from 0 to 4 where Grade 0 was most severe. The
scores depended on ratings for three different categories: functional
impairment, magnitude of task, and magnitude of effort. The TDI scale
administered at each subsequent visit denoted changes from Baseline in
functional impairment, magnitude of task, and magnitude of effort. The
scale ranged from --3 to +3 where negative numbers indicated
deterioration, 0 was no change, and positive numbers indicated
improvement. The ratings for the 3 categories were summed to provide a
Total TDI Score. A difference in TDI scores between treatment groups of
1.0 was considered clinically important (Mahler, 1999; Witek & Mahler,
2001).

#### Chronic Respiratory Disease Questionnaire (CRDQ)

Quality of life was assessed using the CRDQ (Guyatt, 1987) which was
completed at Treatment Day 1 and Weeks 2, 4, 8, and 24 or at the
Discontinuation Visit. The CRDQ is an interviewer-administered
disease-specific validated 20-item questionnaire that evaluates quality
of life across four domains: dyspnea (five items), fatigue (four items),
emotional function (seven items) and mastery over the disease (four
items). For the dyspnea domain, at first administration the subject was
asked to provide five specific activities that they performed regularly
which had been limited by COPD. These individualized activities were
also used to evaluate the subject's dyspnea at subsequent visits. The
responses to the 20 items were summed to provide an overall assessment
of quality of life. A change from Baseline in Overall CRDQ score of
[\>]{.underline}10.0 is considered clinically meaningful (Jaeschke,
1989).

#### Chronic Bronchitis Symptoms Questionnaire (CBSQ)

A new questionnaire (CBSQ) was used to assess changes in frequency and
severity of cough, chest discomfort, and sputum production. The CBSQ
scale combined four selected questions taken from existing
questionnaires (Petty, 1996; Rubin, 1990). The CBSQ evaluated the COPD
symptoms of cough frequency and severity, chest discomfort, and sputum
production on a scale of 0-4, where a rating of 0 reflected no symptoms.
Subjects had to have a score of [\>]{.underline}4 out of a possible 16
at Treatment Day 1 to qualify for the study. The responses to the 4
questions were summed to provide a Global Assessment Score (GAS).
Internal evaluation of unblinded data from study FLTA3025 determined
that the minimum clinically important change (MCIC) from Baseline was
1.4. Test-retest reliability of the CBSQ was assessed and found to be
adequate in study SFCA3007 (correlation \>0.7), however, its sensitivity
to detect change in clinical status was unknown.

### Other Secondary Efficacy Measures

# COPD Exacerbations {#copd-exacerbations .NoNum:Head5}

The occurrence of COPD exacerbations was assessed by the investigator at
each clinic visit. Each COPD exacerbation was categorized as either MILD
(increased use of **VENTOLIN**)*,* MODERATE (use of either oral
antibiotics and/or corticosteroids) or SEVERE (hospitalization). A
subject was discontinued from the study after the first exacerbation
requiring corticosteroids or hospitalization or the third exacerbation
requiring antibiotics. The use of antibiotics for treatment of upper
respiratory tract infections (URTIs) was also considered an
exacerbation.

# Morning Peak Expiratory Flow {#morning-peak-expiratory-flow .NoNum:Head5}

Subjects measured morning peak expiratory flow (PEF) with a hand-held
Mini-Wright Peak Flow Meter and recorded the L/min on their personal
diary card.

# Daily VENTOLIN Use {#daily-ventolin-use .NoNum:Head5}

All subjects were given **VENTOLIN** (aerosol and/or nebules) for use as
needed during the study. Subjects recorded the number of inhalations of
**VENTOLIN** used over the past 24 hours on their personal diary cards.
For data analysis, 1 nebule was equivalent to 3 puffs of aerosol.

# Nighttime Awakenings Requiring VENTOLIN {#nighttime-awakenings-requiring-ventolin .NoNum:Head5}

Subjects also recorded the number of nighttime awakenings due to
symptoms requiring the use of **VENTOLIN** that they experienced during
the previous night on their personal diary card.

## Safety Measures

The safety of the treatments in the three pivotal studies was assessed
by comparing AEs, deaths, SAEs, withdrawals due to AEs, clinical
laboratory tests (including hepatic function, renal function, or
metabolic indices such as serum glucose), HPA axis effects in a subset
of patients (12-hour serum cortisols, cosyntropin stimulation),
cardiovascular measures (12-lead ECG, 24-hour ambulatory ECG in a subset
of patients) and vital signs.

## Statistical Methods

Study enrollment was planned for 175 to 200 per treatment group in each
study. This sample size provides \>90% power to detect differences
between treatment groups of 100mL in both pre-dose and 2-hour post-dose
FEV~1~ at Endpoint. Endpoint was defined as the last on-treatment
post-baseline assessment excluding any data from the discontinuation
visit where additional medications could have been used.

In the individual studies, differences between treatments at Endpoint
and all other time points in the change from baseline in pre-dose and
post-dose FEV~1~, CBSQ, and CRDQ were analyzed using contrasts from
ANCOVA adjusting for baseline and investigator. Analysis of differences
in BDI/TDI was performed using contrasts with ANOVA adjusting for
investigator. Time to first exacerbation and time to withdrawal were
analyzed using Wald Chi-square tests based on a proportional hazards
model adjusting for age and baseline FEV~1~. Overall average and monthly
average AM PEF, nighttime awakenings, and **VENTOLIN** use from the
diary card were analyzed using the van Elteren modification of the
Wilcoxon test to adjust for investigator (van Elteren, 1958). The same
analyses were performed with the integrated data with the exception of
the diary data. AM PEF was analyzed using ANCOVA instead of van Elteren
since the assumption that the data are normally distributed was
considered to be reasonable. **VENTOLIN** use and nighttime awakenings
were analyzed using Wilcoxon instead of van Elteren since van Elteren
would not allow comparison of values not in the same protocol.
Additionally for both the individual studies and integrated data, 95%
confidence intervals were provided for treatment differences in pre-dose
and post-dose FEV~1~ and CRDQ. Baseline by treatment interactions (and
protocol by treatment for the integrated data) were tested and further
examined if warranted for the primary and key secondary measures (except
for the treatment by Baseline interaction for TDI since baseline was not
in the model).

To address multiplicity, in FLTA3025, for the primary efficacy measure
(pre-dose FEV~1~ at Endpoint), the comparison of high dose to placebo
was made before the comparison of low dose to placebo and high dose to
low dose. P-values for the second two comparisons were only interpreted
inferentially if the first comparison was significant.

In SFCA3006 and SFCA3007, p-values for the three main secondary efficacy
measures (overall TDI, CBSQ, and CRDQ scores at Endpoint) were only
interpreted inferentially for each comparison if the corresponding
comparison had a p-value \< 0.05 in the analysis of its primary efficacy
measure (either pre-dose FEV~1~ or post-dose FEV~1~ at Endpoint
depending on the comparison). Additionally, the Hochberg method was used
at the 0.05 level to control the type I error rate across these three
secondary efficacy measures (Hochberg, 1988). Tests of comparisons at
timepoints other than Endpoint were considered supportive.

# STUDY POPULATION OF PIVOTAL CLINICAL STUDIES

In this section, results from the Intent-to-Treat Population are
presented for the three individual studies and the integrated database.
Data from Investigator 1403 in SFCA3006 (17 subjects) was excluded from
all efficacy analyses as there was reason to believe the integrity of
these data may have been compromised. However, these subjects are
included in the safety analyses accounting for the difference in subject
numbers between the safety and efficacy results. Study population
summaries are provided to assist in the evaluation of treatment group
comparability before study treatment.

Summaries of the study population for individual population subgroups
(based on smoking status, bronchodilator response, inhaled
corticosteroid use at Screening, gender, age, and race) are presented in
Section 5.4.

## Subject Accountability

The table below summarizes subject accountability for the ITT Population
in the three pivotal studies and in the integrated data.

  ------------------- -------- ---------- ---------- ---------- ---------- ---------- --
  **Subject                                                                           
  Accountability                                                                      
  Summary\                                                                            
  ITT Population                                                                      
  (excluding                                                                          
  Investigator 1403                                                                   
  in SFCA3006)**                                                                      

                      **\      **\        **\        **\        **FSC\     **FSC\     
                      PLA**    SAL 50**   FP 250**   FP 500**   250/50**   500/50**   

  **SFCA3006**        N=181    N=160                 N=168                 N=165      

  Completed (%)       62       72                    60                    68         

  Discontinued (%)    38       28                    40                    32         

  **SFCA3007**        N=185    N=177      N=183                 N=178                 

  Completed (%)       68       68         73                    70                    

  Discontinued (%)    32       32         27                    30                    

  **FLTA3025**        N=206               N=216      N=218                            

  Completed (%)       62                  65         67                               

  Discontinued (%)    38                  35         33                               

  **Integrated**      N=572    N=337      N=399      N=386      N=178      N=165      

  Completed (%)       64       70         68         64         70         68         

  Discontinued (%)    36       30         32         36         30         32         

  Note: Ns represent                                                                  
  the number of                                                                       
  randomized                                                                          
  subjects.                                                                           
  ------------------- -------- ---------- ---------- ---------- ---------- ---------- --

By the end of the study period, 28% to 40% of each treatment group in
SFCA3006, 27% to 32% of each treatment group in SFCA3007, and 33% to 38%
of each treatment group in FLTA3025 had prematurely discontinued the
study. When study data were integrated, treatment groups were similar
for total numbers of subjects who prematurely discontinued the study
(30% to 36% in each group).

Across the three studies, the most common reason for premature
discontinuation was COPD exacerbation, which were a similar percentage
of the discontinuations across the treatment groups in SFCA3006 (21-27%)
and SFCA3007 (24-30%), and were a higher percentage in the placebo group
(41%) compared with the FP groups (28-29%) in FLTA3025.

## Demographic and Baseline Characteristics

Subjects were required to discontinue use of inhaled corticosteroids at
the Screening Visit. Subjects with a reversible bronchodilator response
demonstrated a post-albuterol increase in FEV~1~ of
[\>]{.underline}200mL and [\>]{.underline}12% from Baseline; all other
subjects were considered non-reversible.

Demographic and baseline characteristics data for the three pivotal
studies and in the integrated data are summarized in the tables below.

  -------------------------- --------- ---------- ----------- --------- ----------- ----------- ---------- -- -- -- --
  **Key Demographics and                                                                                            
  Baseline Characteristics\                                                                                         
  Pivotal Studies - ITT                                                                                             
  Population**                                                                                                      

  **SFCA3006**\              **PLA\               **SAL 50\             **FP 500\               **FSC               
  (excluding Investigator    N=181**              N=160**               N=168**                 500/50\             
  1403)                                                                                         N=165**             

  Gender: % Female/Male      25/75                36/64                 39/61                   38/62               

  Age (yr): Mean             64.0                 63.5                  64.4                    61.9                

  Race: % W/ B/Other         92/6/2               95/4/1                93/5/2                  95/4/1              

  Dyspnea Score: % with 3 or 29                   44                    33                      34                  
  4                                                                                                                 

  ICS use at Screening (%    18                   31                    25                      28                  
  Yes)                                                                                                              

  Former/Current Smokers (%) 46/54                54/46                 54/46                   54/46               

  \# Pack-Yrs: Median        60.0                 52.5                  54.0                    55.0                

  BD Resp: % Rev/Non-Rev     56/44                51/49                 54/46                   53/47               

                                                                                                                    

  **SFCA3007**               **PLA\               **SAL 50\             **FP 250\               **FSC               
                             N=185**              N=177**               N=183**                 250/50\             
                                                                                                N=178**             

  Gender: % Female/Male      32/68                42/58                 34/66                   39/61               

  Age (yr): Mean             64.8                 64.2                  63.3                    63.4                

  Race: % W/ B/Other         94/3/3               93/4/3                91/5/4                  96/3/2              

  Dyspnea Score: % with 3 or 36                   33                    35                      38                  
  4                                                                                                                 

  ICS use at Screening (%    30                   20                    28                      23                  
  Yes)                                                                                                              

  Former/Current Smokers (%) 53/47                49/51                 52/48                   57/43               

  \# Pack-Yrs: Median        56.0                 57.0                  60.0                    53.0                

  BD Resp: % Rev/Non-Rev     55/45                55/45                 55/45                   56/44               

                                                                                                                    

  **FLTA3025**                         **PLA\                 **FP 250\             **FP 500\                       
                                       N=206**                N=216**               N=218**                         

  Gender: % Female/Male                32/68                  28/72                 34/66                           

  Age (yr): Mean                       64.8                   65.2                  63.3                            

  Race: % W/ B/Other                   93/3/2                 94/4/1                94/4/1                          

  Dyspnea Score: % with 3 or           33                     34                    36                              
  4                                                                                                                 

  ICS use at Screening (%              31                     31                    31                              
  Yes)                                                                                                              

  Former/Current Smokers (%)           57/43                  55/45                 53/47                           

  \# Pack-Yrs: Median                  50.0                   54.5                  52.3                            

  BD Resp: % Rev/Non-Rev               60/40                  59/41                 57/43                           

  BD Resp=Bronchodilator                                                                                            
  response, Rev=Reversible.                                                                                         
  Percentages may not add to                                                                                        
  100% due to missing data.                                                                                         
  -------------------------- --------- ---------- ----------- --------- ----------- ----------- ---------- -- -- -- --

  ------------------------ --------- --------- --------- --------- --------- ---------
  **Integrated Data: Key                                                     
  Demographics and                                                           
  Baseline                                                                   
  Characteristics\                                                           
  ITT Population                                                             
  (excluding Investigator                                                    
  1403 in SFCA3006)**                                                        

  **Integrated Data**      **\       **\       **\       **\       **FSC\    **FSC\
                           PLA\      SAL 50\   FP 250\   FP 500\   250/50\   500/50\
                           N=572**   N=337**   N=399**   N=386**   N=178**   N=165**

  Gender: % Female/Male    30/70     39/61     31/69     36/64     39/61     38/62

  Age (yr): Mean           64.6      63.9      64.4      63.8      63.4      61.9

  Race: % W/ B/Other       94/4/2    94/4/2    93/5/3    94/4/2    96/3/2    95/4/1

  Dyspnea Score: % with 3  32        38        35        35        38        34
  or 4                                                                       

  ICS use at Screening (%  27        25        29        28        23        28
  Yes)                                                                       

  Former/Current Smokers   52/48     51/49     54/46     53/47     57/43     54/46
  (%)                                                                        

  \# Pack-Yrs: Median      55        55        57        53        53        55

  BD Resp: % Rev/Non-Rev   57/43     53/47     57/43     55/44     56/44     53/47

  BD Resp=Bronchodilator                                                     
  response,                                                                  
  Rev=Reversible.                                                            
  Percentages may not add                                                    
  to 100% due to missing                                                     
  data.                                                                      
  ------------------------ --------- --------- --------- --------- --------- ---------

Demographic and baseline characteristics for the three individual
studies were similar across the treatment groups and there were no
obvious differences between the three individual studies and the
integrated data.

## Spirometry and Bronchodilator Response at Screening

Spirometric results at Screening, including bronchodilator response, in
the three individual studies and the integrated database are summarized
in the tables below.

  ----------------------- --------- --------- ----------- --------- ----------- ----------- --------------- -- -- -- --
  **Mean Baseline                                                                                                    
  Spirometry and                                                                                                     
  Bronchodilator Response                                                                                            
  Results\                                                                                                           
  Pivotal Studies - ITT                                                                                              
  Population**                                                                                                       

  **SFCA3006**\           **PLA\              **SAL 50\             **FP 500\               **FSC 500/50\            
  (excluding Inv 1403)    N=181**             N=160**               N=168**                 N=165**                  

  Spirometry (n)          N=181               n=160                 N=168                   n=165                    

  Mean FEV~1~ (mL)        1317                1237                  1233                    1268                     

  Mean FEV~1~ % of Pred.  41.5                40.3                  41.4                    40.9                     

  Mean FEV~1~/FVC x 100   49.0                48.6                  47.6                    49.4                     

  BD Response (n)         N=181               n=160                 N=168                   n=165                    

  Mean % increase         19.3                21.2                  19.2                    20.6                     

                                                                                                                     

  **SFCA3007**            **PLA\              **SAL 50\             **FP 250\               **FSC 250/50\            
                          N=185**             N=177**               N=183**                 N=178**                  

  Spirometry (n)          N=185               n=177                 N=183                   n=178                    

  Mean FEV~1~ (mL)        1289                1245                  1313                    1252                     

  Mean FEV~1~ % of Pred.  42.1                41.9                  42.0                    41.4                     

  Mean FEV~1~/FVC x 100   49.6                50.8                  51.27                   49.48                    

  BD Response (n)         N=185               n=176                 N=183                   n=178                    

  Mean % increase         20.2                21.3                  19.5                    20.1                     

                                                                                                                     

  **FLTA3025**                      **PLA\                **FP 250\             **FP 500\                            
                                    N=206**               N=216**               N=218**                              

  Spirometry (n)                    N=206                 n=216                 n=217                                

  Mean FEV~1~ (mL)                  1254                  1242                  1266                                 

  Mean FEV~1~ % of Pred.            41.0                  39.8                  41.3                                 

  Mean FEV~1~/FVC x 100             47.2                  46.6                  47.8                                 

  BD Response (n)                   N=205                 n=214                 n=216                                

  Mean % increase                   22.9                  22.4                  23.3                                 

  Note: BD Response =                                                                                                
  bronchodilator                                                                                                     
  response.\                                                                                                         
  BD response was                                                                                                    
  calculated as                                                                                                      
  post-albuterol FEV~1~                                                                                              
  -- pre-albuterol                                                                                                   
  FEV~1~)/pre-albuterol                                                                                              
  FEV~1~                                                                                                             
  ----------------------- --------- --------- ----------- --------- ----------- ----------- --------------- -- -- -- --

  ----------------------- --------- --------- --------- --------- --------- ---------
  **Integrated Data: Mean                                                   
  Baseline Spirometry and                                                   
  Bronchodilator Response                                                   
  Results\                                                                  
  ITT Population                                                            
  (excluding Investigator                                                   
  1403 in SFCA3006)**                                                       

  **Integrated Data**     **\       **\       **\       **\       **FSC\    **FSC\
                          PLA\      SAL 50\   FP 250\   FP 500\   250/50\   500/50\
                          N=572**   N=337**   N=399**   N=386**   N=178**   N=165**

  Spirometry (n)          n=572     n=337     n=399     n=385     n=178     N=165

  Mean FEV~1~ (mL)        1285      1241      1274      1252      1252      1268

  Mean FEV~1~ % of Pred.  41.5      41.1      40.8      41.3      41.4      40.9

  Mean FEV~1~/FVC x 100   48.6      49.8      48.8      47.7      49.5      49.4

  BD Response (n)         n=571     n=336     n=397     n=384     n=178     N=165

  Mean % increase         20.9      21.3      21.1      21.5      20.1      20.6

  Note: BD Response =                                                       
  bronchodilator                                                            
  response.\                                                                
  BD response was                                                           
  calculated as                                                             
  (post-albuterol FEV~1~                                                    
  -- pre-albuterol                                                          
  FEV~1~)/pre-albuterol                                                     
  FEV~1~                                                                    
  ----------------------- --------- --------- --------- --------- --------- ---------

Baseline spirometry and bronchodilator response data for the three
individual studies were similar across the treatment groups and there
were no obvious differences between the three individual studies and the
integrated data.

## Study Medication Adherence

The table below presents study medication adherence data (based on the
dose counter) for the integrated data.

  ------------------------ ----------- ----------- ----------- ----------- ----------- ----------- --
  **Adherence with Study                                                                           
  Medication\                                                                                      
  ITT Population**                                                                                 
  (excluding Investigator                                                                          
  1403 in SFCA3006)                                                                                

                           **\         **\         **\         **\         **FSC\      **FSC\      
                           PLA**       SAL 50**    FP 250**    FP 500**    250/50**    500/50**    

  **SFCA3006**             **N=181**   **N=160**               **N=168**               **N=165**   

  Median rate (%)          95.2        96.4                    95.9                    95.8        

  ≥90% adherence (%        70          77                      76                      76          
  subjects)                                                                                        

  **SFCA3007**             **N=185**   **N=177**   **N=183**               **N=178**               

  Median rate (%)          96.0        96.4        95.9                    96.0                    

  ≥90% adherence (%        79          82          77                      74                      
  subjects)                                                                                        

  **FLTA3025**             **N=206**               **N=216**   **N=218**                           

  Median rate (%)          96.0                    95.3        95.3                                

  ≥90% adherence (%        73                      79          72                                  
  subjects)                                                                                        

  **Integrated Data**      **N=572**   **N=337**   **N=399**   **N=386**   **N=178**   **N=165**   

  Median rate (%)          95.8        96.4        95.5        95.6        96.0        95.8        

  ≥90% adherence (%        74          80          78          73          74          76          
  subjects)                                                                                        

  **Note:** Adherence rate                                                                         
  = (total doses from dose                                                                         
  counter) / (2 x number                                                                           
  of days on treatment) x                                                                          
  100.                                                                                             
  ------------------------ ----------- ----------- ----------- ----------- ----------- ----------- --

Median treatment adherence was high (95.2% to 96.4%) across all
treatment groups in the three individual studies and the integrated
data.

## Summary of Study Population Results

The results of the clinical trial support the following conclusions
about the study populations and their disposition during the conduct of
the trial.

-   Most subjects completed each individual study ([\>]{.underline}60%
    per treatment group). The percentages of subjects prematurely
    discontinuing the study were similar across the treatment groups.

-   Demographics, baseline characteristics, and baseline spirometry data
    were similar across the treatment groups in each of the three
    studies and there were no obvious differences between the three
    individual studies and integrated data.

-   Medication adherence was high (\>95%) across the treatment groups in
    each of the three studies.

# EFFICACY RESULTS

Efficacy, including quality of life results, are presented for each of
the medications of interest, i.e., **FLOVENT DISKUS** and **ADVAIR
DISKUS**. For each medication, results from each of the individual
studies are first presented for each efficacy measure followed by
presentation of the integrated data from the three studies. The
integrated data support the efficacy results from the individual studies
by providing more precise estimates of the magnitude of treatment
effects and increased sample sizes for examining sub-populations.

In order to account for subject withdrawals, Endpoint results are
presented for primary and key secondary measures (TDI, CRDQ, and CBSQ).
Endpoint was defined as the last on-treatment post-baseline assessment
excluding the Discontinuation Visit. Actual mean differences from the
raw data are reported in the tables. Estimated (model-adjusted) mean
differences, adjusted for site and Baseline, are presented in the text.
P-values in both the tables and text are for adjusted mean differences
that differ slightly from the raw mean differences. Some of the Baseline
sample sizes may differ from the study population data presented in
Section 4 due to subjects with missing Baseline assessments.

Results of the clinical program achieved its primary objective of
demonstrating greater improvements in lung function with the combination
product (**ADVAIR)** compared with each individual component (FP and
salmeterol) alone. Additionally, **ADVAIR** and **FLOVENT** were
superior to placebo.

## FLOVENT DISKUS (FP) Efficacy

The efficacy of FP was compared with PLA in SFCA3006 (FP 500), SFCA3007
(FP 250), and FLTA3025 (FP 500 and FP 250).

### Primary Efficacy Measure: Pre-Dose FEV~1~ 

To evaluate the efficacy of FP, the primary efficacy measure was the
comparison of the mean change from Baseline in pre-dose FEV~1~ for
treatment with FP and PLA at Endpoint. Although the Endpoint comparison
was considered primary, the mean change from Baseline in pre-dose FEV~1~
for treatment with FP and PLA also was assessed at each post-Baseline
treatment visit.

#### Individual Studies

Pre-dose FEV~1~ data at Endpoint are shown in the table below for the
primary comparison of FP 250 and FP 500 vs. PLA.

+------------------+------------+------------+------------+-----------+---+
| ***[Primary      |            |            |            |           |   |
| Compariso        |            |            |            |           |   |
| n]{.underline}*: |            |            |            |           |   |
| Mean Change (mL) |            |            |            |           |   |
| from Baseline\   |            |            |            |           |   |
| Pre-Dose FEV~1~  |            |            |            |           |   |
| at Endpoint**    |            |            |            |           |   |
+------------------+------------+------------+------------+-----------+---+
|                  | **PLA**    | **SAL 50** | **FP 250** | *         |   |
|                  |            |            |            | *FP 500** |   |
+------------------+------------+------------+------------+-----------+---+
| **SFCA3006**     |            |            |            |           |   |
+------------------+------------+------------+------------+-----------+---+
|                  | n=181      | n=159      |            | n=166     |   |
+------------------+------------+------------+------------+-----------+---+
| Baseline Mean    | 1282       | 1192       |            | 1174      |   |
+------------------+------------+------------+------------+-----------+---+
|                  | n=171      | n=158      |            | n=160     |   |
+------------------+------------+------------+------------+-----------+---+
| Endpoint Mean    | 1292       | 1303       |            | 1298      |   |
+------------------+------------+------------+------------+-----------+---+
| Mean Δ           | -4         | 107 ^d^    |            | 109 ^e^   |   |
+------------------+------------+------------+------------+-----------+---+
| **SFCA3007**     |            |            |            |           |   |
+------------------+------------+------------+------------+-----------+---+
|                  | n=185      | n=177      | n=183      |           |   |
+------------------+------------+------------+------------+-----------+---+
| Baseline Mean    | 1232       | 1205       | 1236       |           |   |
+------------------+------------+------------+------------+-----------+---+
|                  | n=172      | n=168      | n=175      |           |   |
+------------------+------------+------------+------------+-----------+---+
| Endpoint Mean    | 1240       | 1303       | 1351       |           |   |
+------------------+------------+------------+------------+-----------+---+
| Mean Δ           | 1          | 91 ^d^     | 109 ^e^    |           |   |
+------------------+------------+------------+------------+-----------+---+
| **FLTA3025**     |            |            |            |           |   |
+------------------+------------+------------+------------+-----------+---+
|                  | n=204      |            | n=215      | n=218     |   |
+------------------+------------+------------+------------+-----------+---+
| Baseline Mean    | 1203       |            | 1207       | 1246      |   |
+------------------+------------+------------+------------+-----------+---+
|                  | n=199      |            | n=211      | n=210     |   |
+------------------+------------+------------+------------+-----------+---+
| Endpoint Mean    | 1221       |            | 1240       | 1301      |   |
+------------------+------------+------------+------------+-----------+---+
| Mean Δ           | 11         |            | 38         | 61 ^e^    |   |
+------------------+------------+------------+------------+-----------+---+
| d\. p\<0.001 for |            |            |            |           |   |
| SAL compared     |            |            |            |           |   |
| with PLA         |            |            |            |           |   |
|                  |            |            |            |           |   |
| e\. p≤0.010 for  |            |            |            |           |   |
| FP compared with |            |            |            |           |   |
| PLA              |            |            |            |           |   |
+------------------+------------+------------+------------+-----------+---+

In all three studies, treatment with FP was associated with greater
improvements in pre-dose FEV~1~ compared with placebo. The estimated
difference in pre‑dose FEV~1~ for FP 500 compared with PLA was 105mL in
SFCA3006 (p\<0.001) and the estimated difference in pre-dose FEV~1~ for
FP 250 compared with PLA was 112mL in SFCA3007 (p\<0.001).

In FLTA3025, a dose-related improvement in pre-dose FEV~1~ compared with
placebo was seen for FP 500 (estimated difference = 57mL, p=0.010)
compared with FP 250 (estimated difference = 32mL, p=0.140).

Results for pre-dose FEV~1~ during the treatment period for the trials
are presented graphically in the figures below.

![](media/image1.wmf)

![](media/image3.wmf){width="5.993055555555555in"
height="4.495833333333334in"}

At Week 1, significantly greater increases in pre-dose FEV~1~ were
observed for treatment with FP 500 compared with PLA in both SFCA3006
and FLTA3025 (p≤0.017, estimated differences = 73 and 40mL) and for
treatment with FP 250 compared with PLA in SFCA3007 (p\<0.001, estimated
difference = 84mL). At Week 24, mean changes from Baseline in pre-dose
FEV~1~ for the FP 500 groups in SFCA3006 and FLTA3025 were 131 and 75mL
compared with ‑18 and 8mL for the PLA groups (p≤0.004, estimated
differences = 127 and 79mL). In SFCA3007, the mean change in pre-dose
FEV~1~ at Week 24 for FP 250 was 118mL compared with 3mL for PLA
(p\<0.001, estimated difference = 116mL).

#### Integrated Data

The integrated results support the efficacy of both FP 500 and FP 250 on
pre-dose FEV~1~ by providing more precise estimates of the magnitude of
the treatment differences than the individual studies. At Endpoint, the
estimated difference between FP 500 and placebo was 85mL with a 95%
confidence interval of (53mL, 118mL), while the estimated difference
between FP 250 and placebo was 73mL with a 95% confidence interval of
(41mL, 105mL). At Week 1 and throughout the study, estimated differences
ranged from 50mL to 109mL between FP 500 and placebo and from 32mL to
81mL between FP 250 and placebo. The largest estimated difference from
placebo for both FP 500 and FP 250 occurred at Week 24, where estimated
differences were 109mL and 81mL, respectively.

The figure below shows the greater increases in pre-dose FEV~1~
throughout the study for the FP treatments compared with PLA.

![](media/image4.wmf){width="5.996527777777778in"
height="4.391666666666667in"}

### Key Secondary Efficacy Measures

#### Baseline/Transition Dyspnea Index (BDI/TDI)

# Individual Studies {#individual-studies-1 .NoNum:Head5}

Key results for the BDI and TDI at Endpoint are presented in the table
below.

+-------------------+-----------+-----------+-----------+-----------+---+
| **Mean of         |           |           |           |           |   |
| Ba                |           |           |           |           |   |
| seline/Transition |           |           |           |           |   |
| Dyspnea Index     |           |           |           |           |   |
| (BDI/TDI)\        |           |           |           |           |   |
| Total TDI Score   |           |           |           |           |   |
| at Endpoint**     |           |           |           |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
|                   | **PLA**   | *         | *         | *         |   |
|                   |           | *SAL 50** | *FP 250** | *FP 500** |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| **SFCA3006**      |           |           |           |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
|                   | n=179     | n=154     |           | n=164     |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| BDI Mean          | 5.8       | 5.9       |           | 6.0       |   |
+-------------------+-----------+-----------+-----------+-----------+---+
|                   | n=172     | n=158     |           | n=161     |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| TDI Mean          | 0.4       | 0.9       |           | 1.3 ^e^   |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| **SFCA3007**      |           |           |           |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
|                   | n=183     | n=176     | n=179     |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| BDI Mean          | 5.7       | 6.1       | 6.2       |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
|                   | n=172     | n=169     | n=175     |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| TDI Mean          | 1.0       | 1.6 ^d^   | 1.7       |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| **FLTA3025**      |           |           |           |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
|                   | n=204     |           | n=213     | n=216     |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| BDI Mean          | 5.8       |           | 6.3       | 5.9       |   |
+-------------------+-----------+-----------+-----------+-----------+---+
|                   | n=199     |           | n=211     | n=211     |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| TDI Mean          | 0.5       |           | 0.9       | 1.2 ^e^   |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| d\. p=0.043 for   |           |           |           |           |   |
| SAL compared with |           |           |           |           |   |
| PLA               |           |           |           |           |   |
|                   |           |           |           |           |   |
| e\. p≤0.010 for   |           |           |           |           |   |
| FP compared with  |           |           |           |           |   |
| PLA               |           |           |           |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+

The estimated differences between treatments with FP 500 and PLA were
1.1 (p=0.005) in SFCA3006 and 0.8 (p=0.010) in FLTA3025. In SFCA3006, a
significant difference in TDI scores between FP 500 (0.8) and PLA (0.1,
p=0.012; estimated difference = 0.6) was observed as early as Week 1.
After Week 8, differences between FP 500 and PLA consistently increased
at each timepoint (p≤0.049). At Week 24 in SFCA3006, the TDI score with
FP 500 (1.9) was significantly greater than that with PLA (0.6,
p\<0.001; estimated difference = 1.5). In FLTA3025, significant
differences in mean TDI total scores were also observed between FP 500
and PLA at most timepoints.

In both SFCA3007 and FLTA3025, the mean TDI scores for treatment with
FP 250 were numerically greater, but not usually significantly
different, from mean TDI scores for PLA. The estimated difference in
SFCA3007 was 0.7 (p=0.057) at Endpoint.

# Integrated Data {#integrated-data-1 .NoNum:Head5}

The integrated results support the efficacy of FP 500 on the TDI and
provide positive evidence for FP 250. At Endpoint, the estimated
difference between FP 500 and placebo was 0.9 for overall TDI score and
ranged from 0.4 to 0.9 throughout the course of the study with the
largest differences occurring at the end of the treatment period. The
estimated difference between FP 250 and placebo was 0.5 at Endpoint, and
ranged from 0.1 to 0.5 throughout the course of the study.

The greater increases over time in mean overall TDI score for the FP
groups compared with the PLA group are depicted in the following figure:

![](media/image5.wmf){width="5.999305555555556in"
height="4.229166666666667in"}

#### Chronic Respiratory Disease Questionnaire (CRDQ)

# Individual Studies {#individual-studies-2 .NoNum:Head5}

The following table summarizes Baseline values and change from Baseline
in CRDQ score for each group in the three clinical studies.

  ------------------ ------------ ------------- ------------ ------------
  **Summary of Mean                                          
  Change from                                                
  Baseline in CRDQ                                           
  Score**                                                    

                     **PLA**      **SAL 50**    **FP 250**   **FP 500**

  **SFCA3006**                                               

  Baseline\          n=177\       n=157\                     n=166\
  Mean               86.2         87.6                       88.5

  Endpoint\          n=175\       n=155\                     n=163\
  Mean\              91.3\        95.8\                      93.5\
  Mean ∆             5.0          8.0                        4.8

  **SFCA3007**                                               

  Baseline\          n=180\       n=173\        n=177\       
  Mean               84.8         86.3          85.5         

  Endpoint\          n=177\       n=170\        n=170\       
  Mean\              89.6\        93.0\         96.4\        
  Mean ∆             5.0          6.4           10.4 ^e^     

  **FLTA3025**                                               

  Baseline\          n=203\                     n=214\       n=213\
  Mean               87.6                       88.8         83.6

  Endpoint\          n=199\                     n=211\       n=210\
  Mean\              89.6\                      94.2\        92.8\
  Mean ∆             1.0                        5.1 ^e^      9.1 ^e^

  e\. p≤0.016 for FP                                         
  compared with PLA                                          
  ------------------ ------------ ------------- ------------ ------------

In FLTA3025, increases in overall CRDQ score at Endpoint were
significantly greater for both FP 250 (5.1) and FP 500 (9.1) compared
with PLA (1.0, p≤0.016, estimated differences=4.3 to 7.3) and approached
the clinically meaningful threshold (≥10) in the FP 500 group. In
SFCA3007, increases in FP 250 (10.4) were clinically meaningful and
significantly greater compared with PLA (5.0, p=0.002; estimated
difference=5.8). In SFCA3006, increases in FP 500 (4.8) were similar to
increases in PLA (5.0, estimated difference=0.5).

# Integrated Data {#integrated-data-2 .NoNum:Head5}

The integrated data support the efficacy on mean increases from Baseline
in overall CRDQ score for both FP 500 and FP 250. At Endpoint, the
estimated difference between FP 500 and placebo was 4.3 with a 95%
confidence interval of (1.8, 6.7), while the estimated difference
between FP 250 and placebo was 4.4 with a 95% confidence interval of
(2.0, 6.8). Estimated differences from placebo at each treatment visit
were smaller than at Endpoint and ranged from 1.5 to 3.3 for FP 500 and
1.2 to 3.8 for FP 250, achieving the largest differences at the end of
the treatment period.

The figure below illustrates the greater mean change in overall CRDQ
score in the FP groups compared with PLA over time.

![](media/image6.wmf){width="5.993055555555555in"
height="4.495833333333334in"}

#### Chronic Bronchitis Symptom Questionnaire (CBSQ)

# Individual Studies {#individual-studies-3 .NoNum:Head5}

The table below presents CBSQ Global Assessment Scores (CBSQ GAS) mean
change from baseline for FP 250 and FP 500 compared with the PLA.

  -------------------- ------------ ------------ ------------ ------------ -- --
  **Summary of Mean                                                           
  Change from Baseline                                                        
  in CBSQ GAS**                                                               

                       **PLA**      **SAL 50**   **FP 250**   **FP 500**      

  **SFCA3006**                                                                

  Baseline             n=180        n=159                     n=167           

  Mean                 7.3          7.4                       7.0             

  Endpoint             n=172        n=158                     n=161           

  Mean                 5.7          5.5                       5.5             

  Mean Change          1.5          1.9                       1.6             

  **SFCA3007**                                                                

  Baseline             n=185        n=177        n=183                        

  Mean                 7.5          7.0          7.4                          

  Endpoint             n=172        n=169        n=175                        

  Mean                 6.1          5.6          5.2                          

  Mean Change          1.4          1.5          2.2 ^e^                      

  **FLTA3025**                                                                

  Baseline             n=205                     n=215        n=218           

  Mean                 7.1                       7.1          7.4             

  Endpoint             n=199                     n=211        n=211           

  Mean                 6.1                       5.7          6.0             

  Mean Change          0.9                       1.4          1.4             

  e\. p=0.006 for FP                                                          
  compared with PLA                                                           
  -------------------- ------------ ------------ ------------ ------------ -- --

Numerically greater increases for mean CBSQ GAS occurred with FP
relative to placebo in each trial, however, significant differences
between the FP and PLA groups for mean CBSQ GAS only occurred
intermittently across the three studies. Only in SFCA3007, a significant
difference was observed for treatment with FP 250 compared with PLA at
Endpoint (p=0.006, estimated difference = 0.8).

# Integrated Data {#integrated-data-3 .NoNum:Head5}

The integrated data provide estimated differences between FP 500 and
placebo and between FP 250 and placebo at Endpoint on the change from
Baseline in the CBSQ GAS of 0.3 and 0.6, respectively. Estimated
differences from placebo ranged from 0.3 to 0.5 for FP 500 and 0.2 to
0.6 for FP 250 across the treatment visits

### Other Secondary Efficacy Measures

#### Incidence of COPD Exacerbations

# Individual Studies {#individual-studies-4 .NoNum:Head5}

The following table summarizes the results for COPD exacerbations of
moderate to severe intensity.

  ------------------- ------------ ------------ ------------ ------------ --
  **Incidence (%) of                                                      
  Moderate or Severe                                                      
  COPD Exacerbation**                                                     

  **Number of\        **\          **\          **\          **\          
  Exacerbations**     PLA**        SAL 50**     FP 250**     FP 500**     

  **SFCA3006**        N=181        N=160                     N=168        

  None                65           63                        60           

  At least One        35           38                        40           

  1                   27           29                        32           

  2                   7            8                         7            

  3                   1            1                         1            

  ≥4                  \<1          0                         0            

  **SFCA3007**        N=185        N=177        N=183                     

  None                66           69           62                        

  At Least One        34           31           38                        

  1                   26           25           30                        

  2                   6            5            8                         

  3                   1            \<1          0                         

  ≥4                  \<1          0            0                         

  **FLTA3025**        N=206                     N=216        N=218        

  None                57                        60           62           

  At Least One        43                        40           38           

  1                   33                        34           30           

  2                   8                         5            7            

  3                   \<1                       1            1            

  ≥4                  0                         \<1          0            
  ------------------- ------------ ------------ ------------ ------------ --

The incidence of moderate or severe COPD exacerbation was comparable
between FP and PLA groups in all three studies.

# Integrated Data {#integrated-data-4 .NoNum:Head5}

As seen with individual study results, the incidence of moderate or
severe COPD exacerbation with the integrated data was comparable between
each FP group and the PLA group.

#### Time-to-Event Analyses

Survival analyses were performed to evaluate potential treatment group
differences in time to first COPD exacerbation and in time to study
withdrawal for any reason), due to COPD exacerbation and due to
COPD-related conditions (defined as withdrawal due to COPD exacerbation
or lack of efficacy). Individual study results and integrated data all
showed no significant differences among treatments for time to first
COPD exacerbation of any intensity, time to first moderate or severe
COPD exacerbation, and time to withdrawal, and time to withdrawal due to
a moderate or severe COPD exacerbation. While no differences were
observed in the individual studies, with integrated data, there was a
significant difference between the FP 250 group and the PLA group for
time to withdrawal for any reason. Additionally in FLTA3025 and the
integrated data, there were significant differences between the FP 500
and PLA groups for time to withdrawal due to a COPD related condition.

#### AM PEF

# Individual Studies {#individual-studies-5 .NoNum:Head5}

The table below summarizes the Baseline values and the Overall mean
change from Baseline for AM PEF for the three clinical studies.

+-------------------+-----------+-----------+-----------+-----------+---+---+
| **Mean Change     |           |           |           |           |   |   |
| (L/min) from      |           |           |           |           |   |   |
| Baseline: Overall |           |           |           |           |   |   |
| PEF**             |           |           |           |           |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
|                   | **PLA**   | *         | *         | *         |   |   |
|                   |           | *SAL 50** | *FP 250** | *FP 500** |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| **SFCA3006**      |           |           |           |           |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
|                   | n=181     | n=158     |           | n=167     |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| Baseline Mean     | 269.5     | 252.1     |           | 243.7     |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
|                   | n=179     | n=157     |           | n=166     |   | [ |
|                   |           |           |           |           |   | ] |
|                   |           |           |           |           |   | { |
|                   |           |           |           |           |   | . |
|                   |           |           |           |           |   | m |
|                   |           |           |           |           |   | a |
|                   |           |           |           |           |   | r |
|                   |           |           |           |           |   | k |
|                   |           |           |           |           |   | } |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| Overall Mean      | 267.1     | 268.7     |           | 256.6     |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| Mean Change       | -2.7      | 16.8 ^d^  |           | 12.9 ^e^  |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| **SFCA3007**      |           |           |           |           |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
|                   | n=184     | n=176     | n=182     |           |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| Baseline Mean     | 220.3     | 210.3     | 220.0     |           |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
|                   | n=183     | n=174     | n=177     |           |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| Overall Mean      | 220.2     | 225.3     | 230.7     |           |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| Mean Change       | 0.8       | 14.7 ^d^  | 11.3 ^e^  |           |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| **FLTA3025**      |           |           |           |           |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
|                   | n=205     |           | n=213     | n=218     |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| Baseline Mean     | 249.6     |           | 254.7     | 254.2     |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
|                   | n=205     |           | n=212     | n=215     |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| Overall Mean      | 247.5     |           | 263.3     | 263.8     |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| Mean Change       | -1.9      |           | 8.8 ^e^   | 9.4 ^e^   |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+
| d\. p\<0.001 for  |           |           |           |           |   |   |
| SAL compared with |           |           |           |           |   |   |
| PLA               |           |           |           |           |   |   |
|                   |           |           |           |           |   |   |
| e\. p≤0.003 for   |           |           |           |           |   |   |
| FP compared with  |           |           |           |           |   |   |
| PLA               |           |           |           |           |   |   |
+-------------------+-----------+-----------+-----------+-----------+---+---+

In all three studies, significantly greater improvements in Overall mean
change in AM PEF were seen with FP treatment relative to placebo, which
confirm the improvements in FEV~1~ reviewed previously. The FP 500 and
FP 250 treatments demonstrated greater increases in AM PEF for each
month of treatment in all three studies; treatment differences were
significant at most timepoints.

# Integrated Data {#integrated-data-5 .NoNum:Head5}

The integrated results for the change from Baseline in Overall AM PEF
and for the change from Baseline at each treatment month support the
efficacy demonstrated in the individual studies. The estimated
difference in the mean change from Baseline in Overall AM PEF between
FP 500 and placebo was 12.6L/min and was 11.4L/min between FP 250 and
placebo. The estimated differences from placebo ranged from 10.7L/min to
14.0L/min for FP 500 and 8.9L/min to 12.3L/min for FP 250 across the 6
monthly average changes from Baseline in AM PEF.

The greater increases in AM PEF for the FP groups over time are depicted
in the following figure:

![](media/image7.wmf){width="5.9944444444444445in"
height="4.445138888888889in"}

#### Daily VENTOLIN Use

# Individual Studies {#individual-studies-6 .NoNum:Head5}

The following table summarizes Baseline values and change from Baseline
in **VENTOLIN** use in the three clinical studies.

+------------------+-----------+-----------+-----------+--------------+
| **Mean Change    |           |           |           |              |
| from Baseline:   |           |           |           |              |
| Total Daily      |           |           |           |              |
| VENTOLIN Use\    |           |           |           |              |
| (Number of Puffs |           |           |           |              |
| of VENTOLIN Used |           |           |           |              |
| per Day)**       |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
|                  | **PLA**   | *         | *         | **FP 500**   |
|                  |           | *SAL 50** | *FP 250** |              |
+------------------+-----------+-----------+-----------+--------------+
| **SFCA3006**     |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Baseline         | n=181     | n=158     |           | n=166        |
+------------------+-----------+-----------+-----------+--------------+
| Mean             | 4.9       | 4.6       |           | 4.5          |
+------------------+-----------+-----------+-----------+--------------+
| Overall          | n=179     | n=157     |           | n=164        |
+------------------+-----------+-----------+-----------+--------------+
| Mean             | 5.4       | 3.6       |           | 4.1          |
+------------------+-----------+-----------+-----------+--------------+
| Mean Change      | 0.5       | -0.9 ^d^  |           | -0.4 ^e^     |
+------------------+-----------+-----------+-----------+--------------+
| **SFCA3007**     |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Baseline         | n=184     | n=176     | n=181     |              |
+------------------+-----------+-----------+-----------+--------------+
| Mean             | 4.8       | 4.6       | 4.6       |              |
+------------------+-----------+-----------+-----------+--------------+
| Overall          | n=182     | n=174     | n=177     |              |
+------------------+-----------+-----------+-----------+--------------+
| Mean             | 5.0       | 3.9       | 4.4       |              |
+------------------+-----------+-----------+-----------+--------------+
| Mean Change      | 0.1       | -0.7 ^d^  | -0.2      |              |
+------------------+-----------+-----------+-----------+--------------+
| **FLTA3025**     |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+
| Baseline         | n=205     |           | n=213     | n=218        |
+------------------+-----------+-----------+-----------+--------------+
| Mean             | 5.4       |           | 5.7       | 5.7          |
+------------------+-----------+-----------+-----------+--------------+
| Overall          | n=204     |           | n=212     | n=215        |
+------------------+-----------+-----------+-----------+--------------+
| Mean             | 6.2       |           | 5.6       | 5.5          |
+------------------+-----------+-----------+-----------+--------------+
| Mean Change      | 0.7       |           | -0.1 ^e^  | -0.2 ^e^     |
+------------------+-----------+-----------+-----------+--------------+
| d\.              |           |           |           |              |
| p[\<]{           |           |           |           |              |
| .underline}0.044 |           |           |           |              |
| for SAL compared |           |           |           |              |
| with PLA         |           |           |           |              |
|                  |           |           |           |              |
| e\.              |           |           |           |              |
| p[\<]{           |           |           |           |              |
| .underline}0.045 |           |           |           |              |
| for FP compared  |           |           |           |              |
| with PLA         |           |           |           |              |
+------------------+-----------+-----------+-----------+--------------+

In all three studies, greater reduction in **VENTOLIN** use was observed
with FP vs. placebo treatments. These differences achieved statistical
significance for FP 500 in FLTA3025 and SFCA3006, but only in FLTA3025
for FP 250. Significant reductions from Baseline in **VENTOLIN** use
were observed at most treatment months for the FP 500 treatment group
compared with the PLA group in SFCA3006 and for both FP treatment groups
compared with the PLA group in FLTA3025 at all timepoints (p≤0.025).

# Integrated Data {#integrated-data-6 .NoNum:Head5}

Results from the integrated data support the efficacy for both FP 500
and FP 250 in the mean change from Baseline in daily **VENTOLIN** use in
contrast to the finding in SFCA3007 for FP 250. Overall daily
**VENTOLIN** use was less for treatments with FP 500 and FP 250 (mean
changes from Baseline of -0.3 and -0.2 puffs per day, respectively)
compared with PLA (mean change from Baseline of 0.5 puffs per day)
(p\<0.001). There were also reductions from Baseline in **VENTOLIN** use
for each month of treatment with both FP 500 and FP 250 compared with
PLA (p≤0.023).

#### Nighttime Awakenings Requiring VENTOLIN

# Individual Studies {#individual-studies-7 .NoNum:Head5}

The following table summarizes Baseline values and change from Baseline
in number of awakenings per night requiring **VENTOLIN** use in the
three clinical studies.

+-------------------+-----------+-----------+-----------+-----------+---+
| **Summary of Mean |           |           |           |           |   |
| Change from       |           |           |           |           |   |
| Baseline in\      |           |           |           |           |   |
| Number of         |           |           |           |           |   |
| Awakenings per    |           |           |           |           |   |
| Night Requiring   |           |           |           |           |   |
| VENTOLIN Use**    |           |           |           |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
|                   | **PLA**   | *         | *         | *         |   |
|                   |           | *SAL 50** | *FP 250** | *FP 500** |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| **SFCA3006**      |           |           |           |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Baseline          | n=177     | n=156     |           | n=163     |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Mean              | 0.27      | 0.26      |           | 0.24      |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Overall           | n=175     | n=153     | []{.mark} | n=162     |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Mean              | 0.36      | 0.17      |           | 0.16      |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Mean Change       | 0.10      | -0.09 ^d^ |           | -0.08 ^e^ |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| **SFCA3007**      |           |           |           |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Baseline          | n=184     | n=175     | n=181     |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Mean              | 0.23      | 0.20      | 0.24      |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Overall           | n=181     | n=174     | n=177     |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Mean              | 0.25      | 0.14      | 0.20      |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Mean Change       | 0.02      | -0.06     | -0.03 ^e^ |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| **FLTA3025**      |           |           |           |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Baseline          | n=202     |           | n=212     | n=217     |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Mean              | 0.22      |           | 0.25      | 0.29      |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Overall           | n=202     |           | n=211     | n=212     |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Mean              | 0.33      |           | 0.20      | 0.25      |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| Mean Change       | 0.11      |           | -0.05 ^e^ | -0.05 ^e^ |   |
+-------------------+-----------+-----------+-----------+-----------+---+
| d\. p\<0.001 for  |           |           |           |           |   |
| SAL compared with |           |           |           |           |   |
| PLA               |           |           |           |           |   |
|                   |           |           |           |           |   |
| e\.               |           |           |           |           |   |
| p[\<]             |           |           |           |           |   |
| {.underline}0.038 |           |           |           |           |   |
| for FP compared   |           |           |           |           |   |
| with PLA          |           |           |           |           |   |
+-------------------+-----------+-----------+-----------+-----------+---+

In all three studies, the FP groups showed a significantly greater
Overall mean decrease in nighttime awakenings requiring **VENTOLIN** use
(-0.03 to --0.08 awakenings per night, respectively) compared with the
mean increase of the PLA groups (0.02 to 0.11 awakenings per night,
respectively) (p≤0.038). During the treatment period in each study, the
FP groups consistently demonstrated greater mean decreases in nighttime
awakenings requiring **VENTOLIN** use compared with the PLA group,
although treatment differences were not significant at all timepoints.

# Integrated Data {#integrated-data-7 .NoNum:Head5}

Results from the integrated data support the efficacy for both FP 500
and FP 250 on nighttime awakenings requiring **VENTOLIN**. The FP 250
and FP 500 groups had fewer Overall nighttime awakenings requiring
**VENTOLIN** use (mean change from Baseline of -0.04 and --0.06
awakenings per night, respectively) compared with the PLA group (mean
change from Baseline of +0.08 awakenings per night) (p\<0.001).
Additionally, both FP treatment groups had fewer awakenings per night
requiring **VENTOLIN** use compared with the PLA treatment group during
each month of the study period (p≤0.041).

## ADVAIR DISKUS (FSC) EFFICACY

### Primary Efficacy Measures

#### Pre-Dose FEV~1~ 

To evaluate the contribution of FP to the efficacy of FSC, the primary
analyses in SFCA3006 and SFCA3007 compared the mean changes from
Baseline in **pre-dose FEV~1~** at Endpoint between the FSC and SAL 50
treatments. Baseline was defined as the pre-dose FEV~1~ on the first
morning of treatment. Mean change from Baseline in pre-dose FEV~1~ at
Endpoint also was compared between FSC and PLA. Although the Endpoint
comparison was considered primary, differences in mean changes from
Baseline in pre-dose FEV~1~ between FSC and both SAL 50 and PLA were
assessed at each post-Baseline treatment visit.

# Individual Studies {#individual-studies-8 .NoNum:Head5}

Pre-dose FEV~1~ data at Endpoint are shown in the following table for
the primary comparison of FSC compared with SAL 50 and FSC compared with
PLA.

+------------+--------+--------+--------+--------+--------+--------+---+
| *          |        |        |        |        |        |        |   |
| **[Primary |        |        |        |        |        |        |   |
| Compa      |        |        |        |        |        |        |   |
| rison:]{.u |        |        |        |        |        |        |   |
| nderline}* |        |        |        |        |        |        |   |
| Mean       |        |        |        |        |        |        |   |
| Change     |        |        |        |        |        |        |   |
| (mL) from  |        |        |        |        |        |        |   |
| Baseline\  |        |        |        |        |        |        |   |
| Pre-Dose   |        |        |        |        |        |        |   |
| FEV~1~ at  |        |        |        |        |        |        |   |
| Endpoint** |        |        |        |        |        |        |   |
+------------+--------+--------+--------+--------+--------+--------+---+
|            | **\    | **\    | **\    | **\    | **FSC\ | **FSC\ |   |
|            | PLA**  | SA     | FP     | FP     | 25     | 50     |   |
|            |        | L 50** |  250** |  500** | 0/50** | 0/50** |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| **         |        |        |        |        |        |        |   |
| SFCA3006** |        |        |        |        |        |        |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| Baseline   | n=181  | n=159  |        | n=166  |        | n=163  |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| Mean       | 1282   | 1192   |        | 1174   |        | 1254   |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| Endpoint   | n=171  | n=158  |        | n=160  |        | n=156  |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| Mean       | 1292   | 1303   |        | 1298   |        | 1410   |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| Mean ∆     | -4     | 107    |        | 109    |        | 156    |   |
|            |        |        |        |        |        | ^      |   |
|            |        |        |        |        |        | a,b,c^ |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| **         |        |        |        |        |        |        |   |
| SFCA3007** |        |        |        |        |        |        |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| Baseline   | n=185  | n=177  | n=183  |        | n=178  |        |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| Mean       | 1232   | 1205   | 1236   |        | 1207   |        |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| Endpoint   | n=172  | n=168  | n=175  |        | n=171  |        |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| Mean       | 1240   | 1303   | 1351   |        | 1375   |        |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| Mean ∆     | 1      | 91     | 109    |        | 165    |        |   |
|            |        |        |        |        | ^a,c^  |        |   |
+------------+--------+--------+--------+--------+--------+--------+---+
| a\.        |        |        |        |        |        |        |   |
| p=0.012    |        |        |        |        |        |        |   |
| for FSC    |        |        |        |        |        |        |   |
| compared   |        |        |        |        |        |        |   |
| with SAL   |        |        |        |        |        |        |   |
|            |        |        |        |        |        |        |   |
| b\.        |        |        |        |        |        |        |   |
| p=0.038    |        |        |        |        |        |        |   |
| for FSC    |        |        |        |        |        |        |   |
| compared   |        |        |        |        |        |        |   |
| with FP    |        |        |        |        |        |        |   |
|            |        |        |        |        |        |        |   |
| c\.        |        |        |        |        |        |        |   |
| p\<0.001   |        |        |        |        |        |        |   |
| for FSC    |        |        |        |        |        |        |   |
| compared   |        |        |        |        |        |        |   |
| with PLA   |        |        |        |        |        |        |   |
+------------+--------+--------+--------+--------+--------+--------+---+

The estimated difference in pre-dose FEV~1~ for FSC 500/50 was 67mL
compared with SAL 50 (p=0.012) and 159mL compared with PLA (p\<0.001).
The estimated difference in pre-dose FEV~1~ for FSC 250/50 was 69mL
compared with SAL 50 (p=0.012) and 161mL compared with PLA (p\<0.001).
Both these estimated differences and the actual increases from baseline
were similar between FSC 500/50 and FSC 250/50.

![](media/image8.wmf)

![](media/image9.wmf)

Significantly greater increases in pre-dose FEV~1~ were observed at Week
1 for treatments with both FSC 500/50 and FSC 250/50 compared with SAL.
This treatment difference was sustained throughout the study.
Substantial increases in pre-dose FEV~1~ at Week 1 with FSC treatment
(165mL for the FSC 250/50 group and 173mL for the FSC 500/50 group)
support an early onset of effect for FSC. Significant differences at
Week 1 between FSC and SAL 50 (p≤0.032, estimated differences = 45mL and
46mL) indicate an early-onset contribution of FP to the efficacy of FSC.
FSC-treated subjects who completed the entire treatment period also
demonstrated substantial increases from Baseline in pre-dose FEV~1~ at
Week 24 (165mL for the FSC 250/50 group and 180mL for the FSC 500/50
group). In both studies, significantly greater increases in pre-dose
FEV~1~ were observed with FSC compared with PLA at Week 1 and at all
timepoints throughout the study.

# Integrated Data {#integrated-data-8 .NoNum:Head5}

The integrated data support the efficacy of FSC on pre-dose FEV~1~ by
providing more precise estimates of the magnitude of the treatment
differences from SAL 50 than the individual studies. At Endpoint, the
estimated difference between FSC 500/50 and SAL 50 was 71mL with a 95%
confidence interval of (23mL, 119mL) and was 66mL with a 95% confidence
interval of (19mL, 113mL) between FSC 250/50 and SAL 50. At Week 1 and
throughout the study, estimated differences ranged from 52mL to 96mL
between FSC 500/50 and SAL 50 and from 23mL to 56mL between FSC 250/50
and SAL 50.

The integrated data also support the efficacy of FSC on pre-dose FEV~1~
by providing more precise estimates of the magnitude of the treatment
differences from placebo than the individual studies. At Endpoint, the
estimated difference between FSC 500/50 and placebo was 148mL with a 95%
confidence interval of (102mL, 195mL) and was 143mL with a 95%
confidence interval of (98mL, 188mL) between FSC 250/50 and placebo. At
Week 1 and throughout the study, estimated differences ranged from 128mL
to 192mL between FSC 500/50 and placebo and from 126mL to 160mL between
FSC 250/50 and placebo.

The greater increases in pre-dose FEV~1~ with the FSC treatments
compared with SAL 50 and with placebo are illustrated in the following
figure:

![](media/image10.wmf)

#### 2-Hour Post-Dose FEV~1~ 

To evaluate the contribution of SAL 50 to the efficacy of FSC, the
primary analyses in SFCA3006 and SFCA3007 compared the mean change from
Baseline at Endpoint in **2‑hour post-dose FEV~1~** between the FSC and
FP treatments. Baseline was defined as the pre-dose FEV~1~ on the first
morning of treatment. In SFCA3006 and SFCA3007 and in integrated data,
the lower strength FSC treatment was compared with the lower strength FP
treatment, and the higher strength FSC treatment was compared with the
higher strength FP treatment. Mean change from Baseline in 2-hour
post-dose FEV~1~ at Endpoint also was compared between FSC and PLA.
Although the Endpoint comparison was considered primary, the mean change
from Baseline in 2-hour post-dose FEV~1~ also was assessed at 2 hours
post-dose on Day 1 and at each subsequent treatment visit.

# Individual Studies {#individual-studies-9 .NoNum:Head5}

Two-hour post-dose FEV~1~ data at Endpoint are shown in the following
table for the primary comparison of FSC compared with FP 250 and FP 500
and FSC compared with PLA.

+------------+-------+-------+-------+-------+----------+----------+
| *          |       |       |       |       |          |          |
| **[Primary |       |       |       |       |          |          |
| Compa      |       |       |       |       |          |          |
| rison:]{.u |       |       |       |       |          |          |
| nderline}* |       |       |       |       |          |          |
| Mean       |       |       |       |       |          |          |
| Change     |       |       |       |       |          |          |
| (mL) from  |       |       |       |       |          |          |
| Baseline\  |       |       |       |       |          |          |
| 2-hour     |       |       |       |       |          |          |
| Post-Dose  |       |       |       |       |          |          |
| FEV~1~ at  |       |       |       |       |          |          |
| Endpoint** |       |       |       |       |          |          |
+------------+-------+-------+-------+-------+----------+----------+
|            | **    | **SAL | **FP  | **FP  | **FSC    | **FSC    |
|            | PLA** |  50** | 250** | 500** | 250/50** | 500/50** |
+------------+-------+-------+-------+-------+----------+----------+
| **         |       |       |       |       |          |          |
| SFCA3006** |       |       |       |       |          |          |
+------------+-------+-------+-------+-------+----------+----------+
| Baseline   | n=181 | n=159 |       | n=166 |          | n=163    |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 1282  | 1192  |       | 1174  |          | 1254     |
+------------+-------+-------+-------+-------+----------+----------+
| Endpoint   | n=171 | n=158 |       | n=160 | [        | n=156    |
|            |       |       |       |       | ]{.mark} |          |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 1324  | 1429  |       | 1327  |          | 1515     |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 28    | 233   |       | 138   |          | 261      |
| Change     |       |       |       |       |          | ^b,c^    |
+------------+-------+-------+-------+-------+----------+----------+
| **         |       |       |       |       |          |          |
| SFCA3007** |       |       |       |       |          |          |
+------------+-------+-------+-------+-------+----------+----------+
| Baseline   | n=185 | n=177 | n=183 |       | n=178    |          |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 1232  | 1205  | 1236  |       | 1207     |          |
+------------+-------+-------+-------+-------+----------+----------+
| Endpoint   | n=172 | n=168 | n=175 |       | n=171    |          |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 1298  | 1413  | 1389  |       | 1490     |          |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 58    | 200   | 147   |       | 281      |          |
| Change     |       |       |       |       | ^a,b,c^  |          |
+------------+-------+-------+-------+-------+----------+----------+
| a\.        |       |       |       |       |          |          |
| p=0.010    |       |       |       |       |          |          |
| for FSC    |       |       |       |       |          |          |
| compared   |       |       |       |       |          |          |
| with SAL   |       |       |       |       |          |          |
|            |       |       |       |       |          |          |
| b\.        |       |       |       |       |          |          |
| p\<0.001   |       |       |       |       |          |          |
| for FSC    |       |       |       |       |          |          |
| compared   |       |       |       |       |          |          |
| with FP    |       |       |       |       |          |          |
|            |       |       |       |       |          |          |
| c\.        |       |       |       |       |          |          |
| p\<0.001   |       |       |       |       |          |          |
| for FSC    |       |       |       |       |          |          |
| compared   |       |       |       |       |          |          |
| with PLA   |       |       |       |       |          |          |
+------------+-------+-------+-------+-------+----------+----------+

The estimated difference in 2-hr post-dose FEV~1~ for FSC 500/50 was 129
mL compared with FP 500 (p\<0.001) and 231mL compared with PLA
(p\<0.001). The estimated difference in 2-hr post-dose FEV~1~ for
FSC 250/50 was 124mL compared with FP 250 (p\<0.001) and 214mL compared
with PLA (p\<0.001). Both these estimated differences and the actual
increases from baseline were similar between treatments with FSC 500/50
and FSC 250/50.

![](media/image11.wmf)

![](media/image12.wmf){width="5.993055555555555in"
height="4.726388888888889in"}

On Day 1, the FSC groups in both studies demonstrated a significantly
greater change from Baseline in 2-hour post-dose FEV~1~ compared with
FP. This treatment difference was sustained throughout the study. The
marked increase in 2‑hour post-dose FEV~1~ on Day 1 with FSC treatment
(206mL for FSC 250/50, 186mL for FSC 500/50) supports a rapid onset of
effect. At Week 24, the mean changes in 2‑hour post-dose FEV~1~ for the
FSC 250/50 and FSC 500/50 groups (293mL and 281mL) were significantly
greater than that of the corresponding strength FP group (161mL and
163mL) (p≤0.003, estimated differences = 107 and 129mL) and compared
with the placebo (p\<0.001, estimated differences = 203mL and 224mL),
indicating sustained improvement in the FSC groups. On Day 1 and at
every timepoint, the FSC treatment group in both studies demonstrated a
significantly greater change from Baseline in 2-hour post-dose FEV~1~
compared with PLA (p\<0.001, estimated differences = 150-267mL). The
sustained increase from Baseline in post-dose FEV~1~ suggests a lack of
tolerance to the bronchodilating effect when FSC is used for a prolonged
period.

# Integrated Data {#integrated-data-9 .NoNum:Head5}

FLTA3025 did not evaluate 2-hour post-dose FEV~1~. Because each FSC and
FP group include subjects from just one study (SFCA3006 or SFCA3007),
results from the analysis of integrated data do not vary much from the
individual study results for post-dose FEV~1~. However, small
inconsequential differences were obtained due to the integration of data
from SFCA3006 and SFCA3007 into the placebo and SAL 50 treatment groups.

At Endpoint, the estimated difference between FSC 500/50 and FP 500 was
130mL with a 95% confidence interval of (73mL, 187mL) and was 125mL with
a 95% confidence interval of (70mL, 179mL) between FSC 250/50 and FP
250. At Day 1 and throughout the study, estimated differences ranged
from 104mL to 176mL between FSC 500/50 and FP 500 and from 96mL to 147mL
between FSC 250/50 and FP 250.

At Endpoint, the estimated difference between FSC 500/50 and placebo was
218mL with a 95% confidence interval of (166mL, 271mL) and was 226mL
with a 95% confidence interval of (175mL, 278mL) between FSC 250/50 and
placebo. At Day 1 and throughout the study, estimated differences ranged
from 138mL to 257mL between FSC 500/50 and placebo and from 163mL to
219mL between FSC 250/50 and placebo.

The greater increases in each FSC group compared with the corresponding
strength of FP and with the placebo group over the course of the study
period are illustrated in the following figure:

![](media/image13.wmf){width="5.996527777777778in"
height="4.708333333333333in"}

### Key Secondary Efficacy Measures

#### Baseline/Transition Dyspnea Index (BDI/TDI)

# Individual Studies {#individual-studies-10 .NoNum:Head5}

Key results for the BDI and TDI at Baseline and at Endpoint are shown in
the table below.

+------------+-------+-------+-------+-------+----------+----------+---+
| **Mean     |       |       |       |       |          |          |   |
| Baseline/  |       |       |       |       |          |          |   |
| Transition |       |       |       |       |          |          |   |
| Dyspnea    |       |       |       |       |          |          |   |
| Index      |       |       |       |       |          |          |   |
| (          |       |       |       |       |          |          |   |
| BDI/TDI) - |       |       |       |       |          |          |   |
| Total      |       |       |       |       |          |          |   |
| Score**    |       |       |       |       |          |          |   |
+------------+-------+-------+-------+-------+----------+----------+---+
|            | **    | **SAL | **FP  | **FP  | **FSC    | **FSC    |   |
|            | PLA** |  50** | 250** | 500** | 250/50** | 500/50** |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| **         |       |       |       |       |          |          |   |
| SFCA3006** |       |       |       |       |          |          |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| Baseline   | n=179 | n=154 |       | n=164 |          | n=160    |   |
| (BDI)      |       |       |       |       |          |          |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| Mean       | 5.8   | 5.9   |       | 6.0   |          | 6.2      |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| Endpoint   | n=172 | n=158 |       | n=161 |          | n=157    |   |
| (TDI)      |       |       |       |       |          |          |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| Mean       | 0.4   | 0.9   |       | 1.3   |          | 2.1      |   |
|            |       |       |       |       |          | ^a\ c^   |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| **         |       |       |       |       |          |          |   |
| SFCA3007** |       |       |       |       |          |          |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| Baseline   | n=183 | n=176 | n=179 |       | n=174    |          |   |
| (BDI)      |       |       |       |       |          |          |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| Mean       | 5.7   | 6.1   | 6.2   |       | 6.1      |          |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| Endpoint   | n=172 | n=169 | n=175 |       | n=172    |          |   |
| (TDI)      |       |       |       |       |          |          |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| Mean       | 1.0   | 1.6   | 1.7   |       | 1.7 ^c^  |          |   |
+------------+-------+-------+-------+-------+----------+----------+---+
| a\.        |       |       |       |       |          |          |   |
| p\<0.001   |       |       |       |       |          |          |   |
| for FSC    |       |       |       |       |          |          |   |
| compared   |       |       |       |       |          |          |   |
| with SAL   |       |       |       |       |          |          |   |
|            |       |       |       |       |          |          |   |
| c\.        |       |       |       |       |          |          |   |
| p≤0.023    |       |       |       |       |          |          |   |
| for FSC    |       |       |       |       |          |          |   |
| compared   |       |       |       |       |          |          |   |
| with PLA   |       |       |       |       |          |          |   |
+------------+-------+-------+-------+-------+----------+----------+---+

The TDI score for treatment with FSC 500/50 was significantly greater
than that for PLA (p\<0.001, estimated difference = 1.7) and SAL 50
(p\<0.001, estimated difference = 1.2). These estimated differences
exceeded the criteria for clinical importance, predefined as a treatment
difference [\>]{.underline}1.0 (Mahler, 1999; Witek & Mahler, 2001).
There was also a trend for a higher TDI score compared with FP treatment
(p=0.033, estimated difference = 0.7). The mean TDI score for treatment
with FSC 500/50 was approximately equal to the sum of the TDI Scores
with each individual component. The estimated difference in TDI Score
between treatments with FSC 250/50 and PLA was 0.8 (p=0.023).
Significant differences in TDI scores between FSC 500/50 and PLA were
observed as early as Week 1 (p\<0.001, estimated difference = 1.4) and
at most time points during the 24 weeks of treatment.

# Integrated Data {#integrated-data-10 .NoNum:Head5}

The integrated results support the efficacy of FSC 500/50 and provide
positive evidence for FSC 250/50. At Endpoint, the estimated differences
in TDI between FSC 500/50 and SAL 50, FP 500, and placebo were 1.1, 0.8,
and 1.7, respectively, and were 0.1, 0.2, and 0.7 between FSC 250/50 and
SAL 50, FP 250, and placebo, respectively.

Estimated differences between FSC 500/50 and placebo ranged from 0.7 to
1.9, from 0.2 to 1.4 between FSC 500/50 and SAL 50, and from 0.2 to 1.0
between FSC 500/50 and FP 500 across the treatment visits. While
estimated differences between FSC 250/50 and its components were
generally small, estimated differences between FSC 250/50 and placebo
ranged from 0.3 to 1.1 across the treatment visits.

The greater increases over time in mean overall TDI score for the FSC
groups compared with the PLA, SAL 50, and the FP groups are depicted in
the following figure:

![](media/image14.wmf){width="5.995833333333334in"
height="4.677083333333333in"}

#### Chronic Respiratory Disease Questionnaire (CRDQ)

# Individual Studies {#individual-studies-11 .NoNum:Head5}

The following table summarizes Baseline values and change from Baseline
in CRDQ score for each group in the three clinical studies.

+-------------+--------+---------+--------+--------+-------+---------+
| **Summary   |        |         |        |        |       |         |
| of Mean     |        |         |        |        |       |         |
| Change from |        |         |        |        |       |         |
| Baseline in |        |         |        |        |       |         |
| CRDQ        |        |         |        |        |       |         |
| Score**     |        |         |        |        |       |         |
+-------------+--------+---------+--------+--------+-------+---------+
|             | **\    | **\     | **\    | **\    | *     | **FSC\  |
|             | PLA**  | S       | FP     | FP     | *FSC\ | 5       |
|             |        | AL 50** |  250** |  500** | 250   | 00/50** |
|             |        |         |        |        | /50** |         |
+-------------+--------+---------+--------+--------+-------+---------+
| *           |        |         |        |        |       |         |
| *SFCA3006** |        |         |        |        |       |         |
+-------------+--------+---------+--------+--------+-------+---------+
| Baseline\   | n=177\ | n=157\  |        | n=166\ |       | n=163\  |
| Mean        | 86.2   | 87.6    |        | 88.5   |       | 87.1    |
+-------------+--------+---------+--------+--------+-------+---------+
| Endpoint\   | n=175\ | n=155\  |        | n=163\ |       | n=161\  |
| Mean\       | 91.3\  | 95.8\   |        | 93.5\  |       | 97.1\   |
| Mean ∆      | 5.0    | 8.0     |        | 4.8    |       | 10.0    |
|             |        |         |        |        |       | ^b\ c^  |
+-------------+--------+---------+--------+--------+-------+---------+
| *           |        |         |        |        |       |         |
| *SFCA3007** |        |         |        |        |       |         |
+-------------+--------+---------+--------+--------+-------+---------+
| Baseline\   | n=180\ | n=173\  | n=177\ |        | n     |         |
| Mean        | 84.8   | 86.3    | 85.5   |        | =175\ |         |
|             |        |         |        |        | 84.1  |         |
+-------------+--------+---------+--------+--------+-------+---------+
| Endpoint\   | n=178\ | n=170\  | n=170\ |        | n     |         |
| Mean\       | 89.6\  | 93.0\   | 96.4\  |        | =169\ |         |
| Mean ∆      | 5.0    | 6.4     | 10.4   |        | 93.9\ |         |
|             |        |         |        |        | 10.0  |         |
|             |        |         |        |        | ^c^   |         |
+-------------+--------+---------+--------+--------+-------+---------+
| b\. p=0.017 |        |         |        |        |       |         |
| for FSC     |        |         |        |        |       |         |
| compared    |        |         |        |        |       |         |
| with FP     |        |         |        |        |       |         |
|             |        |         |        |        |       |         |
| c\. p≤0.007 |        |         |        |        |       |         |
| for FSC     |        |         |        |        |       |         |
| compared    |        |         |        |        |       |         |
| with PLA    |        |         |        |        |       |         |
+-------------+--------+---------+--------+--------+-------+---------+

Treatment with both FSC 500/50 and FSC 250/50 resulted in clinically
meaningful increases, i.e., ≥10.0, from Baseline in overall CRDQ score
that were significantly greater compared with PLA (p≤0.007; estimated
difference=5.3 and 5.2, respectively).

# Integrated Data {#integrated-data-11 .NoNum:Head5}

The integrated data support the efficacy on mean increases from Baseline
in overall CRDQ score for both FSC 500/50 and FSC 250/50 compared with
PLA. At Endpoint, the estimated difference between FSC 500/50 and
placebo was 6.5 with a 95% confidence interval of (3.0, 9.9), while the
estimated difference between FSC 250/50 and placebo was 5.2 with a 95%
confidence interval of (1.8, 8.6). Estimated differences between FSC and
its components ranged from 0.8 to 3.1 at Endpoint with 95% confidence
intervals containing zero. Estimated differences between FSC and PLA at
each treatment visit were smaller than at Endpoint and ranged from 4.6
to 6.2 for FSC 500/50 and 2.0 to 4.0 for FSC 250/50.

The figure below illustrates the greater mean change in overall CRDQ
score in the FSC groups compared with the FP, SAL, and PLA groups over
time.

![](media/image15.wmf){width="5.999305555555556in"
height="4.476388888888889in"}

#### Chronic Bronchitis Symptom Questionnaire (CBSQ)

# Individual Studies {#individual-studies-12 .NoNum:Head5}

The table below presents CBSQ Global Assessment Score (GAS) mean change
from baseline for FSC compared with the individual components and PLA.

  -------------- --------- ------------ ------------ ------------ ---------------- ---------------- --
  **Mean Change                                                                                     
  from Baseline                                                                                     
  in CBSQ GAS**                                                                                     

                 **PLA**   **SAL 50**   **FP 250**   **FP 500**   **FSC 250/50**   **FSC 500/50**   

  **SFCA3006**                                                                                      

  Baseline       n=180     n=159                     n=167                         n=164            

  Mean           7.3       7.4                       7.0                           6.9              

  Endpoint       n=172     n=158                     n=161                         n=157            

  Mean           5.7       5.5                       5.5                           5.1              

  Mean Change    1.5       1.9                       1.6                           1.8 ^c^          

  **SFCA3007**                                                                                      

  Baseline       n=185     n=177        n=183                     n=178                             

  Mean           7.5       7.0          7.4                       7.3                               

  Endpoint       n=172     n=169        n=175                     n=172                             

  Mean           6.1       5.6          5.2                       5.2                               

  Mean Change    1.4       1.5          2.2                       2.1 ^c^                           

  c\. p≤0.047                                                                                       
  for FSC                                                                                           
  compared with                                                                                     
  PLA                                                                                               
  -------------- --------- ------------ ------------ ------------ ---------------- ---------------- --

In both SFCA3006 and SFCA3007, the CBSQ GAS was not statistically
different between the FSC treatment groups and the individual components
and there were only small, but statistically significant, differences
noted between FSC and PLA.

# Integrated Data {#integrated-data-12 .NoNum:Head5}

The integrated data provide an estimated difference of 0.6 between FSC
500/50 and placebo and between FSC 250/50 and placebo at Endpoint on the
change from Baseline in the CBSQ GAS. Estimated differences from placebo
ranged from 0.3 to 1.0 for FSC 500/50 and 0.5 to 1.0 for FSC 250/50
across the treatment visits. Estimated differences between FSC and its
components were generally small and ranged from 0.0 to 0.3 at Endpoint.

### Other Secondary Efficacy Measures

#### Incidence of COPD Exacerbations

# Individual Studies {#individual-studies-13 .NoNum:Head5}

The following table summarizes the results for COPD exacerbations of
moderate to severe intensity.

  ----------------- -------- ---------- ---------- ---------- -------------- --------------
  **Incidence (%)                                                            
  of Moderate or                                                             
  Severe COPD                                                                
  Exacerbation**                                                             

  **Number of\      **\      **\        **\        **\        **\            **\
  Exacerbations**   PLA**    SAL 50**   FP 250**   FP 500**   FSC 250/50**   FSC 500/50**

  **SFCA3006**      N=181    N=160                 N=168                     N=165

  None              65       63                    60                        63

  At least One      35       38                    40                        37

  1                 27       29                    32                        27

  2                 7        8                     7                         8

  3                 1        1                     1                         \<1

  ≥4                \<1      0                     0                         1

  **SFCA3007**      N=185    N=177      N=183                 N=178          

  None              66       69         62                    66             

  At Least One      34       31         38                    34             

  1                 26       25         30                    28             

  2                 6        5          8                     6              

  3                 1        \<1        0                     \<1            

  ≥4                \<1      0          0                     0              
  ----------------- -------- ---------- ---------- ---------- -------------- --------------

In both SFCA3006 and SFCA3007, the incidence of moderate or severe COPD
exacerbation in the FSC group was similar to the incidence in the SAL,
FP, and PLA groups.

# Integrated Data {#integrated-data-13 .NoNum:Head5}

As seen with individual study results, the incidence of moderate or
severe COPD exacerbation with integrated data was comparable between
each FSC group and the SAL, FP, and PLA groups.

#### Time-to-Event Analyses

Survival analyses were also performed to evaluate potential treatment
group differences in time to first COPD exacerbation and study withdraw
for exacerbations of any intensity or moderate/severe COPD
exacerbations. No significant differences between FSC and its components
were observed in the individual studies or integrated data, although
using the integrated data, a difference between FSC 500/50 and placebo
was significant for time to withdrawal due to a COPD-related condition
(defined as COPD exacerbation or lack of efficacy), and differences
between FSC 250/50 and placebo were significant for time to first COPD
exacerbation of any severity, time to withdrawal, and time to withdrawal
due to a COPD-related condition.

#### Morning PEF

# Individual Studies {#individual-studies-14 .NoNum:Head5}

The table below summarizes the Baseline values and the Overall mean
change from Baseline for AM PEF for the three clinical studies.

+------------+-------+-------+-------+-------+----------+----------+---+---+
| **Mean     |       |       |       |       |          |          |   |   |
| Change     |       |       |       |       |          |          |   |   |
| from       |       |       |       |       |          |          |   |   |
| Baseline   |       |       |       |       |          |          |   |   |
| in AM PEF  |       |       |       |       |          |          |   |   |
| (L/min):   |       |       |       |       |          |          |   |   |
| Overall    |       |       |       |       |          |          |   |   |
| PEF**      |       |       |       |       |          |          |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
|            | **    | **SAL | **FP  | **FP  | **FSC    | **FSC    |   |   |
|            | PLA** |  50** | 250** | 500** | 250/50** | 500/50** |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| **         |       |       |       |       |          |          |   |   |
| SFCA3006** |       |       |       |       |          |          |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| Baseline   | n=181 | n=158 |       | n=167 |          | n=162    |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| Mean       | 269.5 | 252.1 |       | 243.7 |          | 254.0    |   |   |
|            |       |       |       |       |          | ^f^      |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| Overall    | n=179 | n=157 | []{.  | n=166 | [        | n=162    |   |   |
|            |       |       | mark} |       | ]{.mark} |          |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| Mean       | 267.1 | 268.7 |       | 256.6 |          | 284.7    |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| Mean       | -2.7  | 16.8  |       | 12.9  |          | 31.9     |   |   |
| Change     |       |       |       |       |          | ^        |   |   |
|            |       |       |       |       |          | a\ b\ c^ |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| **         |       |       |       |       |          |          |   |   |
| SFCA3007** |       |       |       |       |          |          |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| Baseline   | n=184 | n=176 | n=182 |       | n=175    |          |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| Mean       | 220.3 | 210.3 | 220.0 |       | 206.1    |          |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| Overall^b^ | n=183 | n=174 | n=177 |       | n=173    |          |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| Mean       | 220.2 | 225.3 | 230.7 |       | 236.3    |          |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| Mean       | 0.8   | 14.7  | 11.3  |       | 30.6     |          |   |   |
| Change     |       |       |       |       | ^        |          |   |   |
|            |       |       |       |       | a\ b\ c^ |          |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+
| a\.        |       |       |       |       |          |          |   |   |
| p\<0.001   |       |       |       |       |          |          |   |   |
| for FSC    |       |       |       |       |          |          |   |   |
| compared   |       |       |       |       |          |          |   |   |
| with SAL   |       |       |       |       |          |          |   |   |
|            |       |       |       |       |          |          |   |   |
| b\.        |       |       |       |       |          |          |   |   |
| p\<0.001   |       |       |       |       |          |          |   |   |
| for FSC    |       |       |       |       |          |          |   |   |
| compared   |       |       |       |       |          |          |   |   |
| with FP    |       |       |       |       |          |          |   |   |
|            |       |       |       |       |          |          |   |   |
| c\.        |       |       |       |       |          |          |   |   |
| p\<0.001   |       |       |       |       |          |          |   |   |
| for FSC    |       |       |       |       |          |          |   |   |
| compared   |       |       |       |       |          |          |   |   |
| with PLA   |       |       |       |       |          |          |   |   |
+------------+-------+-------+-------+-------+----------+----------+---+---+

Treatment with both FSC 500/50 and FSC 250/50 resulted in significantly
greater mean change from Baseline in Overall AM PEF compared with
treatments with SAL, FP and PLA. In each study, the mean changes from
Baseline in Overall AM PEF with FSC treatment were greater than the sum
of the mean changes from Baseline observed with the SAL and FP
treatments.

# Integrated Data {#integrated-data-14 .NoNum:Head5}

The integrated results for the change from Baseline in Overall AM PEF
and for the change from Baseline at each treatment month support the
efficacy demonstrated in the individual studies. The estimated
differences in the mean change from Baseline in Overall AM PEF between
FSC 500/50 and SAL 50, FP 500, and placebo were 15.6L/min, 19.5L/min,
and 32.0L/min, respectively, and were 13.9L/min, 18.9L/min, and
30.3L/min between FSC 250/50 and SAL 50, FP 250, and placebo,
respectively.

The estimated differences between FSC 500/50 and SAL 50 ranged from
11.5L/min to 18.9L/min, from 13.9L/min to 23.2L/min between FSC 500/50
and FP 500, and from 27.2L/min to 33.9L/min between FSC 500/50 and
placebo across the 6 monthly average changes from Baseline in AM PEF.
For FSC 250/50, the estimated differences from SAL 50 ranged from
11.0L/min to 17.9L/min, from 18.4L/min to 22.4L/min between FSC 250/50
and FP 250, and from 28.2L/min to 32.5L/min between FSC 250/50 and
placebo across the 6 monthly average changes from Baseline in AM PEF.

The figure below illustrates the greater increases in AM PEF with
FSC 250/50 and FSC 500/50 treatments compared with the SAL 50, FP 250,
and FP 500 treatments and compared with PLA throughout the study period.

![](media/image16.wmf)

#### Daily VENTOLIN Use

# Individual Studies {#individual-studies-15 .NoNum:Head5}

The following table summarizes Baseline values and change from Baseline
in Overall **VENTOLIN** use in SFCA3006 and SFCA3007.

+------------+-------+-------+-------+-------+----------+----------+
| **Mean     |       |       |       |       |          |          |
| Change     |       |       |       |       |          |          |
| from       |       |       |       |       |          |          |
| Baseline   |       |       |       |       |          |          |
| in Overall |       |       |       |       |          |          |
| Daily      |       |       |       |       |          |          |
| VENTOLIN   |       |       |       |       |          |          |
| Use\       |       |       |       |       |          |          |
| (Number of |       |       |       |       |          |          |
| Puffs of   |       |       |       |       |          |          |
| VENTOLIN   |       |       |       |       |          |          |
| Used per   |       |       |       |       |          |          |
| Day)**     |       |       |       |       |          |          |
+------------+-------+-------+-------+-------+----------+----------+
|            | **    | **SAL | **FP  | **FP  | **FSC    | **FSC    |
|            | PLA** |  50** | 250** | 500** | 250/50** | 500/50** |
+------------+-------+-------+-------+-------+----------+----------+
| **         |       |       |       |       |          |          |
| SFCA3006** |       |       |       |       |          |          |
+------------+-------+-------+-------+-------+----------+----------+
| Baseline   | n=181 | n=158 |       | n=166 |          | n=161    |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 4.9   | 4.6   |       | 4.5   |          | 4.2      |
+------------+-------+-------+-------+-------+----------+----------+
| Overall    | n=179 | n=157 |       | n=164 |          | n=161    |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 5.4   | 3.6   |       | 4.1   |          | 3.0      |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 0.5   | -0.9  |       | -0.4  |          | -1.2     |
| Change     |       |       |       |       |          | ^b\ c^   |
+------------+-------+-------+-------+-------+----------+----------+
| **         |       |       |       |       |          |          |
| SFCA3007** |       |       |       |       |          |          |
+------------+-------+-------+-------+-------+----------+----------+
| Baseline   | n=184 | n=176 | n=181 |       | n=174    |          |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 4.8   | 4.6   | 4.6   |       | 5.1      |          |
+------------+-------+-------+-------+-------+----------+----------+
| Overall    | n=182 | n=174 | n=177 |       | n=172    |          |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 5.0   | 3.9   | 4.4   |       | 4.1      |          |
+------------+-------+-------+-------+-------+----------+----------+
| Mean       | 0.1   | -0.7  | -0.2  |       | -1.0     |          |
| Change     |       |       |       |       | ^b\ c^   |          |
+------------+-------+-------+-------+-------+----------+----------+
| b\. p≤     |       |       |       |       |          |          |
| 0.036 for  |       |       |       |       |          |          |
| FSC        |       |       |       |       |          |          |
| compared   |       |       |       |       |          |          |
| with FP    |       |       |       |       |          |          |
|            |       |       |       |       |          |          |
| c\.        |       |       |       |       |          |          |
| p≤0.002    |       |       |       |       |          |          |
| for FSC    |       |       |       |       |          |          |
| compared   |       |       |       |       |          |          |
| with PLA   |       |       |       |       |          |          |
+------------+-------+-------+-------+-------+----------+----------+

The mean decrease in Overall **VENTOLIN** use was significantly greater
for treatment with both FSC 500/50 and FSC 250/50 compared with PLA and
FP.

# Integrated Data {#integrated-data-15 .NoNum:Head5}

Results from the integrated data support the efficacy for both FSC
500/50 and FSC 250/50 in the mean change from Baseline in daily
**VENTOLIN** use. Overall daily **VENTOLIN** use was less for treatments
with FSC 500/50 and FSC 250/50 (mean changes from Baseline of -1.2 and
-1.0 puffs per day, respectively) compared with PLA (mean change from
Baseline of 0.5 puffs per day) and FP (mean changes from Baseline of
-0.3 and -0.2 puffs per day) (p[\<]{.underline}0.001). Differences from
the SAL 50 group (mean Overall change from Baseline of -0.8 puffs per
day) were small. There were also reductions from Baseline in
**VENTOLIN** use for each month of treatment with both FSC 500/50 and
FSC 250/50 compared with placebo and FP (p≤0.011).

#### Nighttime Awakenings Requiring VENTOLIN

# individual Studies {#individual-studies-16 .NoNum:Head5}

The following table summarizes Baseline values and change from Baseline
in number of awakenings per night requiring **VENTOLIN** use in SFCA3006
and SFCA3007.

  -------------- --------- ------------ ------------ ------------ ---------------- ----------------
  **Summary of                                                                     
  Mean Change                                                                      
  from Baseline                                                                    
  in Overall\                                                                      
  Number of                                                                        
  Awakenings per                                                                   
  Night                                                                            
  Requiring                                                                        
  VENTOLIN Use**                                                                   

                 **PLA**   **SAL 50**   **FP 250**   **FP 500**   **FSC 250/50**   **FSC 500/50**

  **SFCA3006**                                                                     

  Baseline       n=177     n=156                     n=163                         n=157

  Mean           0.27      0.26                      0.24                          0.22

  Overall        n=175     n=153        []{.mark}    n=162                         n=157

  Mean           0.36      0.17                      0.16                          0.19

  Mean Change    0.10      -0.09                     -0.08                         -0.04 ^c^

  **SFCA3007**                                                                     

  Baseline       n=184     n=175        n=181                     n=174            

  Mean           0.23      0.20         0.24                      0.24             

  Overall        n=181     n=174        n=177                     n=172            

  Mean           0.25      0.14         0.20                      0.12             

  Mean Change    0.02      -0.06        -0.03                     -0.12 ^c^        

  c\. p\<0.001                                                                     
  for FSC                                                                          
  compared with                                                                    
  PLA                                                                              
  -------------- --------- ------------ ------------ ------------ ---------------- ----------------

The mean number of nighttime awakenings was significantly decreased with
both FSC 500/50 and FSC 250/50 treatment compared with PLA.

# Integrated Data {#integrated-data-16 .NoNum:Head5}

Results from the integrated data support the efficacy for both FSC
500/50 and FSC 250/50 on nighttime awakenings requiring **VENTOLIN**
compared to placebo. The FSC 500/50 and FSC 250/50 groups had fewer
Overall nighttime awakenings requiring **VENTOLIN** use (mean change
from Baseline of -0.04 and --0.12 awakenings per night, respectively)
compared with the PLA group (mean change from Baseline of +0.08
awakenings per night) (p\<0.001). Notable differences from the
individual components were generally not observed (the exception being
FSC 250/50 versus FP 250).

## Onset and Duration of Effect

### FP 250 and FP 500

Although there was no formal *a priori* definition for the onset of
effect for FP, the positive effect on mean change from Baseline in
pre-dose FEV~1~ at Week 1 in SFCA3006, SFCA3007, and FLTA3025 was
indicative of an early onset of effect for FP. At Week 1, the integrated
data for the FP 250 and FP 500 treatments show increases in pre-dose
FEV~1~ of 57 and 63mL, respectively. The estimated differences from PLA
for FP 250 and FP 500 were 53 and 61mL with 95% confidence intervals of
(28, 77mL) and (36, 85mL), respectively.

### FSC 500/50 and SAL 50

In order to assess the onset and duration of effect of FSC and of SAL in
the COPD population, 12-hour serial FEV~1~ was performed in a subset of
subjects (n=341) in SFCA3006. The purpose of these measurements was to
demonstrate that SAL‑induced increases in FEV~1~ were sustained for 12
hours with the powder formulations of FSC and SAL in patients with COPD.

On Day 1, the increase in FEV~1~ was ≥100mL in less than 30 minutes
after treatment with both FSC 500/50 and SAL 50. At the end of the 12
hours, subjects treated with either FSC 500/50 or SAL 50 continued to
have improvements from Baseline of 180mL and 145mL, respectively, as
seen in the figure below.

![](media/image17.wmf){width="5.991666666666666in"
height="4.240277777777778in"}

At Week 12, the mean pre-dose FEV~1~ values for FSC 500/50, SAL 50 and
FP 500 were greater than Day 1 baseline by 177, 120, and 77mL,
respectively. At the end of the 12 hours, subjects treated with either
FSC 500/50 or SAL 50 continued to have improvements from baseline of
184mL and 157mL, respectively, as seen in the figure below.

![](media/image18.wmf)

## Efficacy in Population Subgroups

Efficacy results were evaluated for the following population subgroups:
smoking status (current smokers, former smokers), bronchodilator
response (reversible, non-reversible), ICS use (yes, no), gender (male,
female), age (40-64 years, [\>]{.underline}65 years, [\>]{.underline}75
years), and ethnic origin (white, black, other). There were too few
subjects in the nonWhite (Black or Other) and ≥75 years of age subgroups
to determine a response to treatment. In all other population subgroups,
subjects responded to treatment with FSC, SAL, and FP, although the
magnitude of response sometimes differed between subgroups. Results for
smoking status and bronchodilator response subgroups have been selected
for presentation below since differences were seen in the magnitude of
response between the two subgroups, though the trends were consistent
with the results seen in all subjects (FSC [\>]{.underline} FP or SAL \>
PLA).

### Smoking Status

Subjects were required to have [\>]{.underline}20--pack year history of
smoking for study enrollment. Former smokers had discontinued cigarette
smoking for at least 6 months prior to their Screening Visit. Current
smokers were smoking at Screening and continued to smoke throughout the
study. The major findings of this subgroup analysis are as follows:

-   Compared with current smokers, former smokers were generally older,
    had a higher proportion of males, used more inhaled corticosteroids
    at the Screening Visit, and had lower percent predicted FEV~1~.

-   Improvements were observed in most efficacy measures for both former
    and current smokers treated with both FP and FSC compared with
    placebo. Improvements were greater for subjects treated with FSC
    compared with individual components or placebo.

-   For mean change from Baseline in pre-dose FEV~1~, all active
    treatment groups with an FP component had larger magnitudes of
    response relative to placebo within the former smoker subgroup
    compared with the current smoker subgroup.

-   For mean change from Baseline in post-dose FEV~1~, the magnitude of
    response between the active treatment groups and placebo for former
    and current smokers was similar.

### Bronchodilator Response

Bronchodilator response subgroups were based on spirometric response
after inhaling 4 puffs of **VENTOLIN** at Screening. Subjects were
categorized as reversible if they demonstrated a bronchodilator response
(post **VENTOLIN**) of [\>]{.underline}200mL **and** [\>]{.underline}12%
improvement in FEV~1~ over baseline. Subjects were categorized as
non-reversible if they demonstrated a bronchodilator response (post
**VENTOLIN**) that was either \<200mL **or** \<12% improvement in FEV~1~
over baseline. The major findings of this subgroup analysis are as
follows:

-   Compared with non-reversible subjects, reversible subjects were
    generally slightly younger and had a higher proportion of males.

-   Improvements were observed in most efficacy measures for both
    reversible and non-reversible subjects treated with both FP and FSC
    compared with placebo. Improvements were greater for subjects
    treated with FSC compared with individual components or placebo.

-   All active treatments groups in the reversible subgroup had a larger
    magnitude of response relative to placebo compared with the
    non-reversible subgroup for both pre-dose FEV~1~ and post-dose
    FEV~1~, however trends were consistent with that seen in all
    subjects (FSC \>FP or SAL \>PLA).

## Summary of Efficacy

### FP 250 and FP 500

#### Primary Efficacy Measure

**Pre-Dose FEV~1~**. In all three studies, treatment with FP was
associated with greater improvements in pre-dose FEV~1~ compared with
placebo. The estimated difference in pre‑dose FEV~1~ was significantly
greater for FP 500 in SFCA3006 (105mL) and FP 250 in SFCA3007 (112mL)
compared with placebo. In FLTA3025, a dose-related improvement in
pre-dose FEV~1~ was seen as FP 500 had a significantly greater
improvement than placebo (estimated difference = 57mL) while FP 250 did
not (estimated difference = 32mL). When data were integrated, the
estimated differences from placebo for FP 250 and FP 500 were 73mL and
85mL, respectively with 95% confidence intervals of (41mL, 105mL) and
(53mL, 118mL), respectively.

#### Key Secondary Efficacy Measures

**TDI**. A numerical dose response in TDI scores was demonstrated
between FP 250 and FP 500. In SFCA3006 and FLTA3025, treatment with
FP 500 resulted in significantly greater improvements in TDI scores when
compared with PLA at Week 1 and throughout treatment; estimated
differences at Endpoint = 1.1 and 0.8, respectively. No significant
differences were observed for treatment with FP 250 in SFCA3007 or
FLTA3025 at Endpoint.

**CRDQ**. In FLTA3025, increases in overall CRDQ score at Endpoint were
significantly greater for both FP 250 (5.1) and FP 500 (9.1) compared
with PLA (1.0) and approached the clinically meaningful threshold (≥10)
in the FP 500 group. In SFCA3007, increases in FP 250 (10.4) were
clinically meaningful and significantly greater compared with PLA (5.0).
In SFCA3006, increases in FP 500 (4.8) were similar to increases in PLA
(5.0).

**CBSQ GAS**. In SFCA3007, a significant difference was observed at
Endpoint for treatment with FP 250 compared with PLA (estimated
difference = 0.8). No other treatment differences of consequence were
observed in the individual studies. These results indicate that this new
instrument may not be sensitive for discerning treatment effects.

#### Other Secondary Efficacy Measures

**Incidence of COPD Exacerbation**. The incidence of COPD exacerbation
(any intensity) was comparable between the FP and PLA groups in the
three individual studies.

**AM PEF**. Increases in morning PEF for treatment with FP 250 and FP
500 were significantly greater compared with PLA in all the individual
studies.

**Daily VENTOLIN Use**. In SFCA3006 and FLTA3025, treatment with FP 500
resulted in significantly less Overall daily **VENTOLIN** use when
compared with PLA; the difference from PLA was only significant for
FP 250 in FLTA3025.

**Nighttime Awakenings Requiring VENTOLIN Use**. In the three individual
studies, treatment with FP 250 and FP 500 demonstrated significantly
fewer awakenings per night compared with an increase with PLA.

### FSC 250/50 and FSC 500/50

#### Primary Efficacy Measures

**Pre-Dose FEV~1~**. Treatment with FSC 250/50 and FSC 500/50 resulted
in significantly greater improvements in pre-dose FEV~1~ when compared
with SAL 50 at Endpoint; estimated differences = 69 and 67mL,
respectively. The estimated differences at Endpoint for treatment with
FSC 250/50 and FSC 500/50 compared with PLA were 161 and 159mL,
respectively. When data were integrated, the estimated differences at
Endpoint for treatment with FSC 250/50 and FSC 500/50 compared with
SAL 50 were 66 and 71mL, respectively, with 95% confidence intervals of
(19mL, 113mL) and (23mL, 119mL), respectively.

**Post-Dose FEV~1~**. Treatment with FSC 250/50 and FSC 500/50 resulted
in significantly greater improvements in post-dose FEV~1~ when compared
with FP 250 and FP 500 at Day 1 and throughout treatment; estimated
differences at Endpoint = 124 and 129mL, respectively. The estimated
differences at Endpoint for treatment with FSC 250/50 and FSC 500/50
compared with PLA were 214 and 231mL, respectively. Integrated data
supported the greater increases in each FSC group compared with the
corresponding strength of FP and with the placebo group.

#### Key Secondary Efficacy Measures

**TDI**. Treatment with both FSC 250/50 and FSC 500/50 resulted in
dose-related improvement in mean TDI scores at Endpoint that were
significantly greater compared with PLA, estimated differences = 0.8 and
1.7, respectively. Treatment with FSC 500/50 also demonstrated a
significantly higher mean TDI score at Endpoint compared with SAL 50
(estimated difference = 1.2) and numerically greater compared with FP
(estimated difference = 0.7).

**CRDQ**. Treatment with both FSC 500/50 and FSC 250/50 resulted in
clinically meaningful increases (i.e., ≥10.0), from Baseline in overall
CRDQ score that were significantly greater compared with PLA.

**CBSQ GAS**. Treatment with both FSC 250/50 and FSC 500/50 demonstrated
significantly greater mean change from Baseline at Endpoint in GAS
compared with PLA, estimated differences = 0.6 and 0.7, respectively. No
other treatment differences of consequence were observed in the
individual studies.

#### Other Secondary Efficacy Measures

**Incidence of COPD Exacerbation.** The incidence of COPD exacerbations
(any intensity or moderate/severe) for treatment with FSC was similar to
the incidence with SAL, FP, and PLA.

**AM PEF.** Treatment with FSC 500/50 resulted in a significant mean
increase in Overall AM PEF of 31.9L/min compared with mean increases of
16.8L/min and 12.9L/min for SAL 50 and FP 500, respectively, and
compared with a mean decrease (-2.7L/min) in the PLA group. Treatment
with FSC 250/50 resulted in a significant mean increase in Overall AM
PEF of 30.6L/min compared with mean increases of 14.7L/min and 11.3L/min
for SAL 50 and FP 250, respectively, and compared with a slight increase
(0.8L/min) in the PLA group.

**Daily VENTOLIN Use.** Significantly less Overall **VENTOLIN** use was
observed for treatment with FSC 250/50 and FSC 500/50 compared with PLA
and compared with FP 250 and FP 500, respectively. Mean changes from
Baseline in Overall **VENTOLIN** use were --1.0 and --1.2 puffs per day
for FSC 250/50 and FSC 500/50, respectively.

**Nighttime Awakenings Requiring VENTOLIN Use.** The FSC 250/50 and
FSC 500/50 groups had significantly fewer Overall nighttime awakenings
requiring **VENTOLIN** use compared with PLA. Overall mean changes from
Baseline were ‑0.12 and ‑0.04 awakenings per night for the FSC 250/50
and FSC 500/50 groups compared with increases of 0.02 and 0.10
awakenings per night with PLA, respectively.

### Onset and Duration of Effect

-   Efficacy for both FP 250 and FP 500 was observed as early as Week 1.
    At Week 1, the estimated differences from PLA for FP 250 and FP 500
    were 53 and 61mL.

-   The bronchodilating effects of FSC 500/50 and SAL 50 were observed
    at Day 1, indicating an early onset of effect. Twice-daily dosing
    was supported by the maintenance of the effect for 12 hours.

-   No tolerance to the bronchodilator effect was observed over 24 weeks
    of treatment.

# Safety Results

## Introduction and Data Organization

The safety of SAL, FP and FSC **DISKUS** has been evaluated in a total
of 2054 COPD subjects who were randomized and received at least one dose
of study medication in the US controlled studies SFCA3006, SFCA3007 and
FLTA3025. In this section, results in ITT Population are presented for
the three individual studies and the integrated database. Data from
Investigator 1403 in SFCA3006 was excluded from all efficacy analyses as
there was reason to believe the integrity of these data may have been
compromised. However, these subjects are included in the safety analyses
accounting for the difference in subject numbers between the efficacy
and safety results.

Safety information is reported in the following manner:

-   Extent of Exposure: Section 6.2.

-   Adverse Event Experience in Clinical Trials (Section 6.3): This
    section describes adverse events, adverse events of special
    interest, withdrawals due to adverse events and deaths, and serious
    adverse events.

-   Clinical Laboratory Tests: Section 6.4.

-   Summary of Other Safety Assessments (Section 6.5): This section
    includes electrocardiograms, 24-hour Holter monitoring, HPA axis
    effects, and safety in demographic subgroups.

-   Summary of Safety from Clinical Trials: Section 6.6.

## Extent of Exposure

The mean extent of exposure was higher for the active drug treatment
groups compared with the placebo group. The table below presents
exposure to study medication for the 2054 subjects in the ITT
Population. This difference in exposure needs to be considered when
interpreting the adverse events data since subjects with longer duration
of study participation are more likely to experience adverse events than
subjects with shorter duration of study participation.

  ----------------- --------- --------- --------- --------- --------- ---------
  **Extent of                                                         
  Exposure to Study                                                   
  Medication: n                                                       
  (%)\                                                                
  **(ITT Population                                                   
  from SFCA3006,                                                      
  SFCA3007 and                                                        
  FLTA3025                                                            
  Integrated)                                                         

  **\               **\       **\       **\       **\       **FSC\    **FSC\
  \                 PLA\      SAL 50\   FP 250\   FP 500\   250/50\   500/50\
  Subject           N=576**   N=341**   N=399**   N=391**   N=178**   N=169**
  Exposure**                                                          

  **Number of                                                         
  Weeks**                                                             

  0 to \<4 weeks    78 (14)   34 (10)   35 (9)    36 (9)    15 (8)    16 (9)

  4 to \<8 weeks    36 (6)    17 (5)    27 (7)    27 (7)    5 (3)     10 (6)

  8 to \<12 weeks   26 (5)    18 (5)    21 (5)    24 (6)    10 (6)    6 (4)

  12 to \<16 weeks  33 (6)    7 (2)     15 (4)    28 (7)    7 (4)     5 (3)

  16 to \<20 weeks  24 (4)    13 (4)    21 (5)    19 (5)    10 (6)    9 (5)

  20 to \<24 weeks  64 (11)   35 (10)   59 (15)   38 (10)   19 (11)   23 (14)

  ≥24 weeks         315 (55)  217 (64)  221 (55)  219 (56)  112 (63)  100 (59)

                                                                      

  **Treatment                                                         
  Days**                                                              

  Mean              128.9     138.5     135.6     131.9     141.3     137.8

  Range             1-188     1-189     1-227     1-192     1-186     2-191
  ----------------- --------- --------- --------- --------- --------- ---------

## Adverse Event Experience in Clinical Trials

### Introduction

Adverse event information was obtained at each clinic visit by being
spontaneously volunteered by the subject and by asking the subject
general questions about medical problems and concomitant medications.
Diary cards were reviewed at each visit for possible AEs. If the subject
did not mention an event that was recorded, he/she was questioned for
further information in order to determine if an AE occurred.

An AE was defined as any untoward medical occurrence experienced by a
subject administered a pharmaceutical product that did not necessarily
have a causal relationship with this treatment. Any COPD-related signs
and/or symptoms (including COPD exacerbation) that caused a subject to
withdraw from the study (and did not meet the definition of serious)
were not considered AEs because they were symptoms of the disease being
studied. However, if a COPD exacerbation did meet the definition of
serious, as defined by 21 CFR 312.32, it was counted as a serious
adverse event (SAE).

Without knowledge of treatment assignment of the subject, the
Investigator assessed the causality of the adverse event as "yes" (there
was a reasonable possibility that the adverse event may have been caused
by the trial medication) or "no" (there was not a reasonable
possibility).

### Incidence of Adverse Events

The majority of subjects reported at least one AE. The body system with
the highest incidence of AEs was ear, nose and throat.

Upper respiratory tract infection and headaches were the most commonly
reported AEs. Throat irritation, candidiasis mouth/throat, and
hoarseness/dysphonia, all well-documented side effects of inhaled
corticosteroids, occurred with a higher incidence in treatments that
contained FP as compared with the placebo or SAL 50 groups. AEs
(regardless of causality) that occurred with ≥3% incidence in any
treatment group are summarized in the following table.

<table style="width:100%;">
<colgroup>
<col style="width: 27%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 11%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="13"><strong>Summary of Most Common AEs Regardless of Causal
Relationship (≥ 3% incidence): n (%)</strong><br />
(ITT Population from SFCA3006, SFCA3007 and FLTA3025 Integrated)</td>
</tr>
<tr class="even">
<td><strong><br />
<br />
Adverse Event</strong></td>
<td colspan="2"><strong><br />
PLA<br />
N=576</strong></td>
<td colspan="2"><strong><br />
SAL 50<br />
N=341</strong></td>
<td colspan="2"><strong><br />
FP 250<br />
N=399</strong></td>
<td colspan="2"><strong><br />
FP 500<br />
N=391</strong></td>
<td colspan="2"><strong>FSC<br />
250/50<br />
N=178</strong></td>
<td colspan="2"><strong>FSC<br />
500/50<br />
N=169</strong></td>
</tr>
<tr class="odd">
<td colspan="2">ANY EVENT</td>
<td colspan="2">397 (69)</td>
<td colspan="2">233 (68)</td>
<td colspan="2">294 (74)</td>
<td colspan="2">312 (80)</td>
<td colspan="2">124 (70)</td>
<td>131 (78)</td>
</tr>
<tr class="even">
<td colspan="2">URTI</td>
<td colspan="2">85 (15)</td>
<td colspan="2">36 (11)</td>
<td colspan="2">63 (16)</td>
<td colspan="2">70 (18)</td>
<td colspan="2">22 (12)</td>
<td>28 (17)</td>
</tr>
<tr class="odd">
<td colspan="2">Headaches</td>
<td colspan="2">66 (11)</td>
<td colspan="2">47 (14)</td>
<td colspan="2">51 (13)</td>
<td colspan="2">65 (17)</td>
<td colspan="2">28 (16)</td>
<td>30 (18)</td>
</tr>
<tr class="even">
<td colspan="2">Musculoskeletal pain</td>
<td colspan="2">58 (10)</td>
<td colspan="2">42 (12)</td>
<td colspan="2">41 (10)</td>
<td colspan="2">35 (9)</td>
<td colspan="2">16 (9)</td>
<td>20 (12)</td>
</tr>
<tr class="odd">
<td colspan="2">Throat irritation</td>
<td colspan="2">36 (6)</td>
<td colspan="2">24 (7)</td>
<td colspan="2">35 (9)</td>
<td colspan="2">36 (9)</td>
<td colspan="2">15 (8)</td>
<td>19 (11)</td>
</tr>
<tr class="even">
<td colspan="2">Viral respiratory infections</td>
<td colspan="2">23 (4)</td>
<td colspan="2">17 (5)</td>
<td colspan="2">20 (5)</td>
<td colspan="2">36 (9)</td>
<td colspan="2">10 (6)</td>
<td>14 (8)</td>
</tr>
<tr class="odd">
<td colspan="2">URI</td>
<td colspan="2">29 (5)</td>
<td colspan="2">17 (5)</td>
<td colspan="2">21 (5)</td>
<td colspan="2">26 (7)</td>
<td colspan="2">4 (2)</td>
<td>15 (9)</td>
</tr>
<tr class="even">
<td colspan="2">Candidiasis mouth/throat</td>
<td colspan="2">4 (&lt;1)</td>
<td colspan="2">6 (2)</td>
<td colspan="2">23 (6)</td>
<td colspan="2">46 (12)</td>
<td colspan="2">17 (10)</td>
<td>12 (7)</td>
</tr>
<tr class="odd">
<td colspan="2">Nasal congestion/ blockage</td>
<td colspan="2">19 (3)</td>
<td colspan="2">12 (4)</td>
<td colspan="2">17 (4)</td>
<td colspan="2">26 (7)</td>
<td colspan="2">5 (3)</td>
<td>7 (4)</td>
</tr>
<tr class="even">
<td colspan="2">Cough</td>
<td colspan="2">24 (4)</td>
<td colspan="2">17 (5)</td>
<td colspan="2">18 (5)</td>
<td colspan="2">15 (4)</td>
<td colspan="2">2 (1)</td>
<td>6 (4)</td>
</tr>
<tr class="odd">
<td colspan="2">Sinusitis</td>
<td colspan="2">13 (2)</td>
<td colspan="2">15 (4)</td>
<td colspan="2">22 (6)</td>
<td colspan="2">12 (3)</td>
<td colspan="2">6 (3)</td>
<td>5 (3)</td>
</tr>
<tr class="even">
<td colspan="2">Nausea &amp; vomiting</td>
<td colspan="2">18 (3)</td>
<td colspan="2">11 (3)</td>
<td colspan="2">16 (4)</td>
<td colspan="2">16 (4)</td>
<td colspan="2">4 (2)</td>
<td>6 (4)</td>
</tr>
<tr class="odd">
<td colspan="2">Diarrhea</td>
<td colspan="2">28 (5)</td>
<td colspan="2">11 (3)</td>
<td colspan="2">12 (3)</td>
<td colspan="2">12 (3)</td>
<td colspan="2">3 (2)</td>
<td>4 (2)</td>
</tr>
<tr class="even">
<td colspan="2">Chest symptoms</td>
<td colspan="2">24 (4)</td>
<td colspan="2">12 (4)</td>
<td colspan="2">9 (2)</td>
<td colspan="2">15 (4)</td>
<td colspan="2">4 (2)</td>
<td>6 (4)</td>
</tr>
<tr class="odd">
<td colspan="2">Hoarseness/dysphonia</td>
<td colspan="2">6 (1)</td>
<td colspan="2">2 (&lt;1)</td>
<td colspan="2">18 (5)</td>
<td colspan="2">19 (5)</td>
<td colspan="2">9 (5)</td>
<td>5 (3)</td>
</tr>
<tr class="even">
<td colspan="2">Fever</td>
<td colspan="2">18 (3)</td>
<td colspan="2">4 (1)</td>
<td colspan="2">12 (3)</td>
<td colspan="2">11 (3)</td>
<td colspan="2">8 (4)</td>
<td>6 (4)</td>
</tr>
<tr class="odd">
<td colspan="2">Malaise &amp; fatigue</td>
<td colspan="2">17 (3)</td>
<td colspan="2">7 (2)</td>
<td colspan="2">11 (3)</td>
<td colspan="2">12 (3)</td>
<td colspan="2">6 (3)</td>
<td>6 (4)</td>
</tr>
<tr class="even">
<td colspan="2">Muscle cramps &amp; spasms</td>
<td colspan="2">7 (1)</td>
<td colspan="2">10 (3)</td>
<td colspan="2">9 (2)</td>
<td colspan="2">8 (2)</td>
<td colspan="2">6 (3)</td>
<td>13 (8)</td>
</tr>
<tr class="odd">
<td colspan="2">Rhinitis</td>
<td colspan="2">14 (2)</td>
<td colspan="2">12 (4)</td>
<td colspan="2">11 (3)</td>
<td colspan="2">8 (2)</td>
<td colspan="2">4 (2)</td>
<td>3 (2)</td>
</tr>
<tr class="even">
<td colspan="2">Dizziness</td>
<td colspan="2">10 (2)</td>
<td colspan="2">12 (4)</td>
<td colspan="2">7 (2)</td>
<td colspan="2">7 (2)</td>
<td colspan="2">7 (4)</td>
<td>5 (3)</td>
</tr>
<tr class="odd">
<td colspan="2">Hypertension</td>
<td colspan="2">11 (2)</td>
<td colspan="2">12 (4)</td>
<td colspan="2">5 (1)</td>
<td colspan="2">9 (2)</td>
<td colspan="2">4 (2)</td>
<td>5 (3)</td>
</tr>
<tr class="even">
<td colspan="2">Sinusitis/sinus infection</td>
<td colspan="2">11 (2)</td>
<td colspan="2">5 (1)</td>
<td colspan="2">8 (2)</td>
<td colspan="2">7 (2)</td>
<td colspan="2">3 (2)</td>
<td>7 (4)</td>
</tr>
<tr class="odd">
<td colspan="2">Muscle pain</td>
<td colspan="2">5 (&lt;1)</td>
<td colspan="2">4 (1)</td>
<td colspan="2">7 (2)</td>
<td colspan="2">13 (3)</td>
<td colspan="2">0</td>
<td>7 (4)</td>
</tr>
<tr class="even">
<td colspan="2">Ear signs &amp; symptoms</td>
<td colspan="2">6 (1)</td>
<td colspan="2">11 (3)</td>
<td colspan="2">6 (2)</td>
<td colspan="2">4 (1)</td>
<td colspan="2">4 (2)</td>
<td>4 (2)</td>
</tr>
<tr class="odd">
<td colspan="13"><p>Note: Most common defined as incidence ≥3% (before
rounding) in any treatment group</p>
<p>URTI = Upper respiratory tract infection; URI = upper respiratory
inflammation</p>
<p>Viral respiratory infections was the preferred term for flu or flu
symptoms; URI includes all AEs of ‘cold symptoms’</p>
<p>The preferred term “chest symptoms” includes chest pain, chest
tightness, and anxiety chest pains.</p></td>
</tr>
</tbody>
</table>

### Adverse Events of Special Interest

For subjects using inhaled corticosteroids, AEs of special interest
include candida infection, hoarseness/dysphonia, throat irritation,
evidence of bone loss, cataracts, glaucoma, and HPA axis suppression. A
summary of the AEs of special interest (with the exception of HPA axis
suppression; see Section 6.5.2) is provided in the following table.

  ---------------------- --------- --------- --------- --------- --------- ---------
  **AEs of Special                                                         
  Interest: n (%)**\                                                       
  (ITT Population from                                                     
  SFCA3006, SFCA3007 and                                                   
  FLTA3025 Integrated)                                                     

  **\                    **\       **\       **\       **\       **FSC\    **FSC\
  \                      PLA\      SAL 50\   FP 250\   FP 500\   250/50\   500/50\
  Adverse Event**        N=576**   N=341**   N=399**   N=391**   N=178**   N=169**

  Candidiasis            6 (1)     8 (2)     29 (7)    50 (13)   20 (11)   18 (11)

  Throat irritation      36 (6)    24 (7)    35 (9)    36 (9)    15 (8)    19 (11)

  Hoarseness/dysphonia   6 (1)     2 (\<1)   18 (5)    19 (5)    9 (5)     5 (3)

  Fractures              9 (2)     1 (\<1)   4 (1)     4 (1)     3 (2)     3 (2)

  Cataracts              1 (\<1)   0         0         3 (\<1)   0         0

  Ocular pressure        2 (\<1)   0         0         0         0         2 (1)
  disorders                                                                

  Note: Candidiasis                                                        
  includes candidiasis                                                     
  (mouth/throat),                                                          
  candidiasis                                                              
  unspecified, and                                                         
  unspecified                                                              
  oropharyngeal plaques                                                    
  ---------------------- --------- --------- --------- --------- --------- ---------

As expected, a higher incidence of total candidiasis (includes
candidiasis \[mouth/throat\], candidiasis unspecified, and unspecified
oropharyngeal plaques) occurred in the treatment groups receiving FP
compared with subjects receiving placebo or SAL.

Throat irritation and hoarseness/dysphonia, well-documented side effects
of inhaled corticosteroids, also occurred with a slightly higher
incidence in the FP and/or FSC groups compared with the placebo or SAL
50 groups.

Few fractures were reported during the study and the incidence was
comparable across the treatment groups. As expected for a 6-month trial,
none of the fractures were considered treatment related.

Cataracts were reported by one subject (adverse event: bilateral
cataracts) in the placebo group and three subjects (adverse events:
worsening cataracts; cataract exacerbation; cataract right eye) in the
FP 500 group. All three FP-treated subjects had cataracts listed as a
concurrent medical condition at Screening. Ocular pressure disorders
were noted in two subjects each in the placebo (adverse events:
glaucoma; elevated intraocular pressure) and FSC 500/50 (adverse events:
pigment dispersion syndrome; glaucoma) groups.

### Withdrawals Due to Adverse Events

A total of 136 subjects (7%) were withdrawn due to AEs. With the
exception of FP 500, a comparable incidence of AEs resulting in
withdrawal were noted across the treatment groups.

COPD exacerbation was the most common AE leading to withdrawal. No other
AE led to withdrawal in \>1% of subjects. AEs that led to withdrawal in
more than two subjects across the treatment groups are summarized in the
following table.

+----------------------+-------+-------+-------+-------+------+------+
| **Most Common AEs    |       |       |       |       |      |      |
| Leading to Study     |       |       |       |       |      |      |
| Withdrawal: n (%)**\ |       |       |       |       |      |      |
| (ITT Population from |       |       |       |       |      |      |
| SFCA3006, SFCA3007   |       |       |       |       |      |      |
| and FLTA3025         |       |       |       |       |      |      |
| Integrated)          |       |       |       |       |      |      |
+----------------------+-------+-------+-------+-------+------+------+
| **\                  | **\   | **\   | **\   | **\   | **   | **   |
| AE Leading to Study  | PLA\  | SAL   | FP    | FP    | FSC\ | FSC\ |
| Withdrawal**         | N=    | 50\   | 250\  | 500\  | 250  | 500  |
|                      | 576** | N=    | N=    | N=    | /50\ | /50\ |
|                      |       | 341** | 399** | 391** | N=1  | N=1  |
|                      |       |       |       |       | 78** | 69** |
+----------------------+-------+-------+-------+-------+------+------+
| ANY EVENT            | 36    | 15    | 23    | 42    | 9    | 11   |
|                      | (6)   | (4)   | (6)   | (11)  | (5)  | (7)  |
+----------------------+-------+-------+-------+-------+------+------+
| COPD exacerbation    | 8 (1) | 4 (1) | 8 (2) | 10    | 0    | 2    |
|                      |       |       |       | (3)   |      | (1)  |
+----------------------+-------+-------+-------+-------+------+------+
| Pneumonia            | 1     | 1     | 4 (1) | 4 (1) | 0    | 2    |
|                      | (\<1) | (\<1) |       |       |      | (1)  |
+----------------------+-------+-------+-------+-------+------+------+
| Depressive disorders | 3     | 0     | 0     | 2     | 0    | 0    |
|                      | (\<1) |       |       | (\<1) |      |      |
+----------------------+-------+-------+-------+-------+------+------+
| Hoarseness/dysphonia | 1     | 0     | 0     | 3     | 1    | 0    |
|                      | (\<1) |       |       | (\<1) | (    |      |
|                      |       |       |       |       | \<1) |      |
+----------------------+-------+-------+-------+-------+------+------+
| Fractures            | 0     | 1     | 1     | 1     | 2    | 0    |
|                      |       | (\<1) | (\<1) | (\<1) | (1)  |      |
+----------------------+-------+-------+-------+-------+------+------+
| Breathing disorders  | 2     | 0     | 0     | 1     | 0    | 1    |
|                      | (\<1) |       |       | (\<1) |      | (    |
|                      |       |       |       |       |      | \<1) |
+----------------------+-------+-------+-------+-------+------+------+
| URTI                 | 0     | 1     | 1     | 2     | 0    | 0    |
|                      |       | (\<1) | (\<1) | (\<1) |      |      |
+----------------------+-------+-------+-------+-------+------+------+
| Candidiasis          | 0     | 0     | 0     | 3     | 0    | 0    |
| mouth/throat         |       |       |       | (\<1) |      |      |
+----------------------+-------+-------+-------+-------+------+------+
| Viral respiratory    | 0     | 0     | 1     | 1     | 1    | 0    |
| infections           |       |       | (\<1) | (\<1) | (    |      |
|                      |       |       |       |       | \<1) |      |
+----------------------+-------+-------+-------+-------+------+------+
| Cardiovascular test  | 2     | 1     | 0     | 0     | 0    | 0    |
| findings             | (\<1) | (\<1) |       |       |      |      |
+----------------------+-------+-------+-------+-------+------+------+
| Cerebrovascular      | 0     | 1     | 1     | 1     | 0    | 0    |
| accidents            |       | (\<1) | (\<1) | (\<1) |      |      |
+----------------------+-------+-------+-------+-------+------+------+
| Myocardial           | 1     | 0     | 1     | 1     | 0    | 0    |
| infarction           | (\<1) |       | (\<1) | (\<1) |      |      |
+----------------------+-------+-------+-------+-------+------+------+
| Palpitations         | 2     | 0     | 0     | 1     | 0    | 0    |
|                      | (\<1) |       |       | (\<1) |      |      |
+----------------------+-------+-------+-------+-------+------+------+
| Tachyarrhythmias     | 1     | 1     | 0     | 0     | 0    | 1    |
|                      | (\<1) | (\<1) |       |       |      | (    |
|                      |       |       |       |       |      | \<1) |
+----------------------+-------+-------+-------+-------+------+------+
| Throat irritation    | 1     | 0     | 0     | 2     | 0    | 0    |
|                      | (\<1) |       |       | (\<1) |      |      |
+----------------------+-------+-------+-------+-------+------+------+
| Chest symptoms       | 1     | 0     | 0     | 1     | 0    | 2    |
|                      | (\<1) |       |       | (\<1) |      | (1)  |
+----------------------+-------+-------+-------+-------+------+------+
| Note: URTI = Upper   |       |       |       |       |      |      |
| respiratory tract    |       |       |       |       |      |      |
| infection            |       |       |       |       |      |      |
|                      |       |       |       |       |      |      |
| The preferred term   |       |       |       |       |      |      |
| "chest symptoms"     |       |       |       |       |      |      |
| includes chest pain, |       |       |       |       |      |      |
| chest tightness, and |       |       |       |       |      |      |
| anxiety chest pains. |       |       |       |       |      |      |
+----------------------+-------+-------+-------+-------+------+------+

### Deaths and Serious Adverse Events

Four deaths were reported in the controlled clinical studies (one
subject died after completing study FLTA3025 and SFCA3006 and two deaths
occurred during SFCA3006; no subjects died in SFCA3007). All four deaths
occurred in subjects treated with placebo; no deaths occurred in the
active drug treatment groups. None of the deaths were considered by the
investigator to be related to study drug.

-   FLTA3025: Approximately 17 days after her final study visit, Subject
    38176, a 72‑year-old female previously treated with placebo, died
    due to ovarian adenocarcinoma. The subject presented to the
    emergency room complaining of abdominal pain. Subsequent
    hospitalization revealed adenocarcinoma in the ascitic fluid that
    was originating from the ovary. She was discharged 6 days later and
    her prognosis was poor. Two days after discharge, the subject died.

-   SFCA3006: Seven weeks after initiating treatment with placebo,
    Subject 10798, a 66‑year-old female, developed severe lower
    abdominal pain. Study drug was discontinued 8 days later. She was
    admitted to the hospital and was diagnosed with adenocarcinoma of
    the small intestines. She died as a result of the adenocarcinoma
    approximately 1 month after onset of abdominal pain.

-   SFCA3006: Six days after initiating treatment with placebo, Subject
    11283, a 60‑year-old male, was admitted to the hospital due to
    chronic anemia. A colonoscopy revealed multiple colonic tumors and
    he subsequently underwent a subtotal colectomy with ileal
    proctostomy. Although initially stable and extubated, the subject
    was reintubated for aspiration pneumonia. Study drug was
    discontinued and the subject died approximately 2 months later due
    to aspiration pneumonia.

-   SFCA3006: Twelve weeks after initiating treatment with placebo,
    Subject 11379, a 69‑year-old male, experienced difficulty
    swallowing, dysphagia, and laryngitis. A laryngoscopy revealed
    bilateral vocal cord paralysis that resulted in hospitalization.
    Diagnostic studies revealed a recurrence of his thyroid cancer.
    Study drug was discontinued and the subject underwent surgical
    resection and a tracheostomy. He did not receive radiation or
    chemotherapy and his prognosis was poor. The subject died
    approximately 7 months later due to the thyroid cancer.

A total of 115 subjects (115/2054, 6%) experienced at least one SAE
during the treatment period; of these, 75 subjects were withdrawn due to
their SAEs (25 from FLTA3025, 29 from SFCA3006, and 21 from SFCA3007). A
comparable proportion of SAEs were reported for subjects across the six
treatment groups. SAEs that were reported for more than one subject in
any treatment group are shown in the following table.

  ------------------ --------- --------- --------- --------- --------- ---------
  **SAEs Reported by                                                   
  More Than One                                                        
  Subject in Any                                                       
  Treatment Group: n                                                   
  (%)**\                                                               
  (ITT Population                                                      
  from SFCA3006,                                                       
  SFCA3007 and                                                         
  FLTA3025                                                             
  Integrated)                                                          

  **\                **\       **\       **\       **\       **FSC\    **FSC\
  \                  PLA\      SAL 50\   FP 250\   FP 500\   250/50\   500/50\
  SAE**              N=576**   N=341**   N=399**   N=391**   N=178**   N=169**

  ANY EVENT          34 (6)    12 (4)    25 (6)    27 (7)    8 (4)     9 (5)

  COPD exacerbation  7 (1)     4 (1)     8 (2)     11 (3)    0         2 (1)

  Pneumonia          1 (\<1)   1 (\<1)   3 (\<1)   4 (1)     0         2 (1)

  Chest symptoms     5 (\<1)   1 (\<1)   0         0         1 (\<1)   2 (1)

  Fractures          1 (\<1)   0         2 (\<1)   2 (\<1)   1 (\<1)   0

  Cholelithiasis     1 (\<1)   0         2 (\<1)   0         0         0

  Syncope            0         0         2 (\<1)   0         0         0

  Depressive         2 (\<1)   0         0         0         0         0
  disorders                                                            

  Note: The                                                            
  preferred term                                                       
  "chest symptoms"                                                     
  includes chest                                                       
  pain, chest                                                          
  tightness, and                                                       
  anxiety chest                                                        
  pains.                                                               
  ------------------ --------- --------- --------- --------- --------- ---------

As expected, the most common SAE was COPD exacerbation. COPD
exacerbation was reported by [\<]{.underline}3% of subjects. Pneumonia
and chest symptoms were reported as SAEs in [\<]{.underline}1% of
subjects; the remaining SAEs were each reported by \<1% of subjects in
any treatment group. Details on the SAEs of fractures can be found in
Section 6.3.3, Adverse Events of Special Interest.

Only one subject experienced a SAE during the treatment period that was
considered to be drug related:

-   SFCA3006: Five weeks after initiating study treatment with SAL 50,
    Subject 9060, a 71‑year-old male with a history of angina and
    coronary artery disease, was hospitalized with angina and a
    subsequent cardiac catheterization revealed three stenotic coronary
    vessels with the worst being a 75% lesion. Two coronary stents were
    placed. The event was considered life-threatening, disabling and
    incapacitating. Study drug was discontinued and the event resolved 2
    days after onset. In the investigator\'s opinion, the angina was
    possibly related to the use of study drug, but also possibly caused
    by a history of cardiovascular disease.

## Clinical Laboratory Tests

### Laboratory Data Collection and Analysis

Analyses of laboratory results via two different methods (shift analysis
relative to the normal range and sponsor pre-defined threshold
laboratory values) revealed no clinically relevant effects of active
treatment on clinical chemistry and hematology analytes collected at the
Screening Visit, Week 12, and Week 24 and/or the Discontinuation Visit.

Because of the known effects associated with the administration of
beta~2~-agonists and inhaled corticosteriods on glucose and potassium
metabolism, sponsor defined threshold analyses for blood glucose and
potassium are presented in this document.

### Sponsor-defined Threshold Analyses for Potassium and Glucose

The following table presents the frequency of laboratory values outside
the threshold values for potassium and glucose. The sponsor defined
threshold values for potassium and glucose were [\<]{.underline}3Meq/L;
[\>]{.underline}6Meq/L and \<55mg/dL; \> 175mg/dL, respectively.

  ----------------- --------- --------- --------- --------- --------- ---------
  **Number of                                                         
  Subjects with                                                       
  Potassium and                                                       
  Glucose Outside                                                     
  Sponsor-Defined                                                     
  Threshold Values                                                    
  at Any Visit                                                        
  Post-Baseline: n                                                    
  (%)\                                                                
  **(ITT Population                                                   
  from SFCA3006,                                                      
  SFCA3007 and                                                        
  FLTA3025                                                            
  Integrated)                                                         

  **Hematology      **\       **\       **\       **\       **FSC\    **FSC\
  Parameter**       PLA\      SAL 50\   FP 250\   FP 500\   250/50\   500/50\
                    N=576**   N=341**   N=399**   N=391**   N=178**   N=169**

  **Potassium**\    n=548\    n=325\    n=382\    n=374\    n=169\    n=162\
  \> threshold      2 (\<1)\  0\        1 (\<1)\  0\        1 (\<1)\  0\
  range\            0         0         0         0         0         0
  \< threshold                                                        
  range                                                               

  **Glucose**\      n=550\    n=326\    n=382\    n=374\    n=170\    n=162\
  \> threshold      13 (2)\   11 (3)\   11 (3)\   13 (3)\   3 (2)\    7 (4)\
  range\            3 (\<1)   5 (2)     2 (\<1)   1 (\<1)   1 (\<1)   1 (1)
  \< threshold                                                        
  range                                                               
  ----------------- --------- --------- --------- --------- --------- ---------

A similar percentage of subjects exhibited glucose values that exceeded
the threshold limit across treatment groups. There were no subjects in
any treatment group with a potassium value below the threshold limit.

## Summary of Other Safety Assessments

### Cardiovascular Monitoring

#### 12-Lead Electrocardiograms (ECGs)

A 12-lead ECG was recorded at the Screening Visit, and pre-dose at
Week 12, Week 24 and/or the Subject Discontinuation Visit. In addition
to the initial evaluation of the ECG by the investigator, an independent
electrocardiographer, blinded to treatment assignment, was responsible
for providing measurements of heart rate, PR interval, QTc, QRS
duration, and an overall interpretation of each ECG. For
post-randomization ECGs, the independent electrocardiographer compared
each ECG to the pre-randomization ECG to determine whether or not a
clinically significant change had occurred. If any clinically
significant worsening was noted post-randomization, the ECG was repeated
and the investigator advised the subject of clinically appropriate
follow-up.

An abnormal, clinically significant ECG was defined as a 12-lead tracing
showing evidence of myocardial ischemia, left or right ventricular
hypertrophy, clinically significant conduction abnormalities (e.g., left
bundle branch block, Wolff-Parkinson-White syndrome), or clinically
significant arrhythmias (e.g., atrial fibrillation, ventricular
tachycardia). Subjects with a clinically significant abnormal ECG at the
Screening Visit were ineligible for this study. ECG qualitative results
are summarized in the following table.

  --------------------- --------- --------- --------- --------- --------- ---------
  **ECG Qualitative                                                       
  Results: n (%)\                                                         
  **(ITT Population                                                       
  from SFCA3006,                                                          
  SFCA3007 and FLTA3025                                                   
  Integrated)                                                             

  **\                   **\       **\       **\       **\       **FSC\    **FSC\
  \                     PLA\      SAL 50\   FP 250\   FP 500\   250/50\   500/50\
  Timepoint**           N=576**   N=341**   N=399**   N=391**   N=178**   N=169**

  **Baseline**                                                            

  n                     576       341       398       390       177       169

  Normal                272 (47)  185 (54)  227 (57)  226 (58)  89 (50)   94 (56)

  Abnormal, not CS      300 (52)  155 (45)  169 (42)  160 (41)  88 (50)   75 (44)

  Abnormal CS           4 (\<1)   1 (\<1)   2 (\<1)   4 (1)     0         0

  **Week 12**                                                             

  n                     418       265       307       289       140       133

  Normal                196 (47)  152 (57)  162 (53)  160 (55)  75 (54)   77 (58)

  Abnormal, not CS      214 (51)  113 (43)  140 (46)  128 (44)  65 (46)   54 (41)

  Abnormal CS           8 (2)     0         5 (2)     1 (\<1)   0         2 (2)

  CS change from BL     5 (1)     0         3 (\<1)   0         0         1 (1)

  **Week 24**                                                             

  n                     360       234       264       247       118       113

  Normal                168 (47)  117 (50)  134 (51)  126 (51)  65 (55)   60 (53)

  Abnormal, not CS      187 (52)  117 (50)  126 (48)  117 (47)  53 (45)   53 (47)

  Abnormal CS           5 (1)     0         4 (2)     4 (2)     0         0

  CS change from BL     3 (\<1)   0         2 (\<1)   3 (1)     0         0

  **Discontinuation**                                                     

  n                     178       87        104       123       38        50

  Normal                87 (49)   36 (41)   46 (44)   55 (45)   19 (50)   26 (52)

  Abnormal, not CS      84 (47)   47 (54)   57 (55)   65 (53)   19 (50)   23 (46)

  Abnormal CS           7 (4)     4 (5)     1 (\<1)   3 (2)     0         1 (2)

  CS change from BL     6 (3)     2 (2)     1 (\<1)   2 (2)     0         1 (2)

  Note: CS = clinically                                                   
  significant; BL =                                                       
  baseline                                                                
  --------------------- --------- --------- --------- --------- --------- ---------

Few subjects had a clinically significant change in ECG results at Week
12, Week 24 or at Discontinuation. Overall, the incidence of clinically
significant abnormalities was lower for those treated with SAL (1%;
seven of 688 subjects who received either SAL 50 or FSC 500/50; no
clinically significant abnormalities were observed in the FSC 250/50
group) compared with placebo (3%; 16 of 576 subjects).

Mean QTc intervals calculated using either Bazett's (QTcB) or
Fridericia's (QTcF) correction were similar across the treatment groups
at all time points. Mean and change from Baseline (including categorical
changes) in QTcB intervals during the study are summarized in the
following in-text table.

+-------------+--------+--------+--------+--------+--------+--------+
| **QTcB      |        |        |        |        |        |        |
| Interval    |        |        |        |        |        |        |
| Mean and    |        |        |        |        |        |        |
| Categorical |        |        |        |        |        |        |
| Change from |        |        |        |        |        |        |
| Baseline\   |        |        |        |        |        |        |
| (ITT        |        |        |        |        |        |        |
| Population  |        |        |        |        |        |        |
| from        |        |        |        |        |        |        |
| SFCA3006,   |        |        |        |        |        |        |
| SFCA3007    |        |        |        |        |        |        |
| and         |        |        |        |        |        |        |
| FLTA3025    |        |        |        |        |        |        |
| In          |        |        |        |        |        |        |
| tegrated)** |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| **\         | **\    | **\    | **\    | **\    | **FSC\ | **FSC\ |
| \           | PLA\   | SAL    | FP     | FP     | 2      | 5      |
| Timepoint** | N      | 50\    | 250\   | 500\   | 50/50\ | 00/50\ |
|             | =576** | N      | N      | N      | N      | N      |
|             |        | =341** | =399** | =391** | =178** | =169** |
+-------------+--------+--------+--------+--------+--------+--------+
| **          | 415    | 417    | 415    | 417    | 417    | 418    |
| Baseline**\ |        |        |        |        |        |        |
| Mean        |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| **Week      | N=417\ | N=263\ | N=307\ | N=289\ | N=140\ | N=133\ |
| 12**\       | 414\   | 414\   | 413\   | 414\   | 415\   | 419\   |
| Mean\       | -0.1\  | -2.3\  | -2.2\  | -2.7\  | -1.8\  | 1.7\   |
| Change from | \      | \      | \      | \      | \      | \      |
| BL\         | 395    | 257    | 297    | 275    | 135    | 124    |
| Category:\  | (95%)\ | (97%)\ | (97%)\ | (95%)\ | (96%)\ | (93%)\ |
| \<30msec\   | 18     | 4      | 8      | 11     | 3      | 7      |
| 30-50msec\  | (4%)\  | (2%)\  | (3%)\  | (4%)\  | (2%)\  | (5%)\  |
| 50-70msec\  | 3      | 1      | 1      | 2      | 2      | 1      |
| [\>]{.under | (      | (      | (      | (      | (1%)\  | (1%)\  |
| line}70msec | \<1%)\ | \<1%)\ | \<1%)\ | \<1%)\ | 0      | 1 (1%) |
|             | 1      | 1      | 1      | 0      |        |        |
|             | (\<1%) | (\<1%) | (\<1%) |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| **Week      | N=360\ | N=234\ | N=264\ | N=248  | N=119\ | N=113\ |
| 24**\       | 412\   | 415\   | 412\   |        | 414\   | 416\   |
| Mean\       | -2.0\  | -1.9\  | -3.1\  | 413\   | -2.7\  | -1.1\  |
| Change from | \      | \      | \      | -2.7\  | \      | \      |
| BL\         | 346    | 227    | 251    | \      | 117    | 110    |
| Category:\  | (96%)\ | (97%)\ | (95%)\ | 238    | (98%)\ | (97%)\ |
| \<30msec\   | 10     | 3      | 12     | (96%)\ | 2      | 3      |
| 30-50msec\  | (3%)\  | (1%)\  | (5%)\  | 8      | (2%)\  | (3%)\  |
| 50-70msec\  | 4      | 3      | 0\     | (3%)\  | 0\     | 0\     |
| [\>]{.under | (1%)\  | (1%)\  | 1      | 0\     | 0      | 0      |
| line}70msec | 0      | 1      | (\<1%) | 1      |        |        |
|             |        | (\<1%) |        | (\<1%) |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| **Discont   | N=177\ | N=87\  | N=104\ | N=123\ | N=38\  | N=50\  |
| inuation**\ | 413\   | 416\   | 414\   | 415\   | 418\   | 417\   |
| Mean\       | -3.9\  | -2.7\  | -4.0\  | -6.3\  | -2.1\  | -1.0\  |
| Change from | \      | \      | \      | \      | \      | \      |
| BL\         | 168    | 86     | 100    | 118    | 37     | 46     |
| Category:\  | (95%)\ | (99%)\ | (97%)\ | (96%)\ | (97%)\ | (92%)\ |
| \<30msec\   | 7      | 1      | 2      | 4      | 1      | 4      |
| 30-50msec\  | (4%)\  | (1%)\  | (2%)\  | (3%)\  | (3%)\  | (8%)\  |
| 50-70msec\  | 2      | 0\     | 0\     | 1      | 0\     | 0\     |
| [\>]{.under | (1%)\  | 0      | 1      | (      | 0      | 0      |
| line}70msec | 0      |        | (\<1%) | \<1%)\ |        |        |
|             |        |        |        | 0      |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Note: any   |        |        |        |        |        |        |
| decreases   |        |        |        |        |        |        |
| from        |        |        |        |        |        |        |
| Baseline    |        |        |        |        |        |        |
| are         |        |        |        |        |        |        |
| included in |        |        |        |        |        |        |
| the         |        |        |        |        |        |        |
| \<30msec    |        |        |        |        |        |        |
| category    |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+

Mean QTcB intervals were similar across the treatment groups at Baseline
and during the study. The majority of subjects across treatment groups
(\>92%) had a change from Baseline of less than 30msec in QTcB
intervals. Few subjects across treatment groups ([\<]{.underline}1%) had
a change from Baseline in QTcB interval [\>]{.underline}70msec.

#### Continuous Ambulatory Electrocardiography (Holter)

Continuous ambulatory electrocardiographic (Holter) monitoring was
performed on 158 subjects at 18 study centers in study SFCA3006. A
baseline Holter monitoring of 24-hour duration was performed at some
time during the single-blind run-in period. Subjects with clinically
significant abnormal findings were not randomized into the study.
Post-treatment Holter monitoring was performed at Treatment Week 4.
Monitoring was initiated approximately 1 hour
([+]{.underline}15 minutes) prior to the administration of the morning
dose of study medication and continued for 24 hours.

The majority of subjects ([\>]{.underline}95% per treatment group at
Screening and [\>]{.underline}89% at Week 4) had ECG data (as determined
by Holter monitoring) that were within the normal limits. Five subjects
experienced significant changes from Screening in Holter monitoring: one
subject (3%) in the placebo group, one subject (3%) in the SAL 50 group,
two subjects (6%) in the FP 500 group, and one subject (4%) in the FSC
500/50 group. One subject experienced atrial fibrillation/flutter (FP
500 group), one subject experienced heart block (FSC 500/50 group), and
three subjects experienced non-sustained ventricular tachycardia (one
subject in the placebo group, one subject in the SAL 50 group, one
subject in the FP 500 group).

***Cardiac Rhythm Abnormalities***

The median number of ventricular ectopic (VE) events were comparable
across the treatment groups at Screening and did not change appreciably
following 4 weeks of treatment. The number of VE couplets (two
ventricular ectopic beats preceded and followed by regular beats)
experienced by subjects at Screening and Week 4 was similar between
treatment groups. The number of VE runs (three ventricular ectopic beats
preceded and followed by regular beats) experienced by subjects at
Screening was less in the SAL 50 group compared with the other groups
and less in the FSC 500/50 group at Week 4 compared with the other
groups. The median number of supraventricular ectopic (SVE) events were
comparable across the treatment groups at Screening and did not change
with treatment. The median number of VE and SVE events are provided in
the following in-text table.

+---------------+-----+-----+-----+------+-----+-----+-----+------+
| **Summary of  |     |     |     |      |     |     |     |      |
| Cardiac       |     |     |     |      |     |     |     |      |
| Rhythm        |     |     |     |      |     |     |     |      |
| Abnormalities |     |     |     |      |     |     |     |      |
| (in 24 hours) |     |     |     |      |     |     |     |      |
| Determined by |     |     |     |      |     |     |     |      |
| Holter        |     |     |     |      |     |     |     |      |
| Monitoring\   |     |     |     |      |     |     |     |      |
| **ITT         |     |     |     |      |     |     |     |      |
| Population    |     |     |     |      |     |     |     |      |
| from SFCA3006 |     |     |     |      |     |     |     |      |
+---------------+-----+-----+-----+------+-----+-----+-----+------+
|               | *   |     |     |      | **W |     |     |      |
|               | *Sc |     |     |      | eek |     |     |      |
|               | ree |     |     |      | 4** |     |     |      |
|               | nin |     |     |      |     |     |     |      |
|               | g** |     |     |      |     |     |     |      |
+---------------+-----+-----+-----+------+-----+-----+-----+------+
|               | **\ | **  | *   | *    | **\ | **  | *   | *    |
|               | P   | SAL | *FP | *FSC | P   | SAL | *FP | *FSC |
|               | LA\ | 50\ | 5   | 500  | LA\ | 50\ | 5   | 500  |
|               | N   | N   | 00\ | /50\ | N   | N   | 00\ | /50\ |
|               | =18 | =16 | N   | N=1  | =18 | =16 | N   | N=1  |
|               | 5** | 4** | =17 | 69** | 5** | 4** | =17 | 69** |
|               |     |     | 3** |      |     |     | 3** |      |
+---------------+-----+-----+-----+------+-----+-----+-----+------+
| n with        | 44  | 38  | 39  | 37   | 35  | 31  | 35  | 29   |
| Holters       |     |     |     |      |     |     |     |      |
+---------------+-----+-----+-----+------+-----+-----+-----+------+
| Median No. of | 1   | 1   | 1   | 11.0 | 2   | 1   | 2   | 9.0  |
| VEs           | 6.0 | 2.0 | 0.0 |      | 0.0 | 5.0 | 1.0 |      |
+---------------+-----+-----+-----+------+-----+-----+-----+------+
| VE couplets   | 9   | 8   | 8   | 8    | 5   | 8   | 8   | 5    |
+---------------+-----+-----+-----+------+-----+-----+-----+------+
| VE runs       | 7   | 3   | 8   | 10   | 7   | 7   | 10  | 3    |
+---------------+-----+-----+-----+------+-----+-----+-----+------+
| No. of subj   | 16  | 13  | 13  | 9    | 13  | 10  | 13  | 10   |
| with\         |     |     |     |      |     |     |     |      |
| \>50 VEs      |     |     |     |      |     |     |     |      |
+---------------+-----+-----+-----+------+-----+-----+-----+------+
| Median No. of | 1   | 1   | 8.0 | 14.0 | 1   | 1   | 1   | 8.0  |
| SVEs          | 3.5 | 1.0 |     |      | 9.0 | 1.0 | 1.0 |      |
+---------------+-----+-----+-----+------+-----+-----+-----+------+
| No. of subj   | 15  | 10  | 10  | 9    | 10  | 9   | 9   | 6    |
| with\         |     |     |     |      |     |     |     |      |
| \>50 SVEs in  |     |     |     |      |     |     |     |      |
| 24hr          |     |     |     |      |     |     |     |      |
+---------------+-----+-----+-----+------+-----+-----+-----+------+
| Note: VE =    |     |     |     |      |     |     |     |      |
| ventricular   |     |     |     |      |     |     |     |      |
| ectopic       |     |     |     |      |     |     |     |      |
| (event); SVE  |     |     |     |      |     |     |     |      |
| =             |     |     |     |      |     |     |     |      |
| sup           |     |     |     |      |     |     |     |      |
| raventricular |     |     |     |      |     |     |     |      |
| ectopic       |     |     |     |      |     |     |     |      |
| (event)       |     |     |     |      |     |     |     |      |
|               |     |     |     |      |     |     |     |      |
| VE couplets = |     |     |     |      |     |     |     |      |
| two           |     |     |     |      |     |     |     |      |
| ventricular   |     |     |     |      |     |     |     |      |
| ectopic beats |     |     |     |      |     |     |     |      |
| preceded and  |     |     |     |      |     |     |     |      |
| followed by   |     |     |     |      |     |     |     |      |
| regular beats |     |     |     |      |     |     |     |      |
|               |     |     |     |      |     |     |     |      |
| VE runs =     |     |     |     |      |     |     |     |      |
| three or more |     |     |     |      |     |     |     |      |
| ventricular   |     |     |     |      |     |     |     |      |
| ectopic beats |     |     |     |      |     |     |     |      |
| preceded and  |     |     |     |      |     |     |     |      |
| followed by   |     |     |     |      |     |     |     |      |
| regular beats |     |     |     |      |     |     |     |      |
+---------------+-----+-----+-----+------+-----+-----+-----+------+

***Cardiac Rate***

Cardiac rates overall were comparable between treatment groups at
Screening and Week 4. The overall average (average of the hourly means)
heart rate at Week 4 was 79.23 beats per minute (bpm) for the placebo
group, 81.54bpm for the SAL 50 group, 82.98bpm for the FP 500 group, and
81.19bpm for the FSC 500/50 group. Cardiac rates overall were comparable
between treatment groups at Screening (p=0.623) and Week 4 (p=0.490).

#### Effects on Vital Signs

Twelve-hour serial vital signs were obtained from SFCA3006 sites that
participated in 12-hour serial spirometry testing. Median changes from
Baseline in systolic blood pressure, diastolic blood pressure and heart
rate were similar across the treatment groups and ranged from --14 to
2mmHg, --3 to 2mmHg, and --2 to 6bpm, respectively.

### HPA Axis Effects

Hypothalmic-pituitary-adrenal (HPA) axis effects were evaluated in
SFCA3006, SFCA3007 and FLTA3025. At a subset of sites in SFCA3006 and
SFCA3007, morning plasma cortisol concentrations and short cosyntropin
stimulation testing were evaluated at Treatment Day 1 (pre-treatment)
and Endpoint (Treatment Week 24 or Discontinuation Visit). For
cosyntropin stimulation testing, threshold values of 14.5mcg/dl and
5.6mcg/dl were used in this analysis instead of the values stated in the
cosyntropin package insert (18.0 mcg/dl and 7 mcg/dl) because an HPLC
assay was used. The values used in the cosyntropin package insert were
based on a less specific RIA assay and need to be adjusted downward when
using a more specific HPLC assay. This adjustment is consistent with
previously published data (Pulmicort Package Insert, 1998; Scott, 1999).
In FLTA3025, blood samples were obtained from subjects for plasma FP and
serum cortisol analyses no earlier than Treatment Week 4 at eight
pre-selected sites. These results are described in Section 2.2.

#### SFCA3006 and SFCA3007

***Cortisol levels***

At both Day 1 (pre-treatment) and at Endpoint, plasma cortisol
concentrations were comparable across the treatment groups at both pre-
and post-stimulation. The majority of subjects had normal cortisol
levels at Day 1 (pre-treatment) and at Endpoint.

#### Abnormalities in Short ACTH stimulation

***Abnormalities in Short ACTH Stimulation for All Subjects:***
Abnormalities in short ACTH stimulation at Day 1 (pre-treatment) and
Endpoint are presented for all subjects in the following in-text table.
A few subjects had abnormalities in short ACTH stimulation test results
at Baseline or Endpoint with no consistent or dose-related differences
observed across the treatment groups.

+--------------------------+-------+------+------+------+------+-----+
| **Number of Subjects     |       |      |      |      |      |     |
| With Abnormalities in    |       |      |      |      |      |     |
| Short ACTH Stimulation   |       |      |      |      |      |     |
| Test Results: n (%)\     |       |      |      |      |      |     |
| **(ITT Population from   |       |      |      |      |      |     |
| SFCA3006 and SFCA3007    |       |      |      |      |      |     |
| Integrated)              |       |      |      |      |      |     |
+--------------------------+-------+------+------+------+------+-----+
|                          | **\   | **\  | **\  | **\  | **   | **  |
|                          | PLA\  | SAL  | FP   | FP   | FSC\ | FSC |
|                          | N=    | 50\  | 250\ | 500\ | 250  | 5   |
|                          | 576** | N=3  | N=3  | N=3  | /50\ | 00/ |
|                          |       | 41** | 99** | 91** | N=1  | 50\ |
|                          |       |      |      |      | 78** | N   |
|                          |       |      |      |      |      | =16 |
|                          |       |      |      |      |      | 9** |
+--------------------------+-------+------+------+------+------+-----+
| **Day 1                  |       |      |      |      |      |     |
| (Pre-treatment)**        |       |      |      |      |      |     |
+--------------------------+-------+------+------+------+------+-----+
| n with cortisols         | 98    | 89   | 50   | 39   | 44   | 39  |
+--------------------------+-------+------+------+------+------+-----+
| AM cortisol \<4mcg/dL    | 3 (3) | 1    | 2    | 0    | 0    | 1   |
|                          |       | (1)  | (4)  |      |      | (3) |
+--------------------------+-------+------+------+------+------+-----+
| Post-stim change         | 5 (5) | 11   | 5    | 2    | 4    | 4   |
| \<5.6mcg/dL              |       | (12) | (10) | (5)  | (9)  | (   |
|                          |       |      |      |      |      | 10) |
+--------------------------+-------+------+------+------+------+-----+
| Post-stim cortisol       | 3 (3) | 4    | 3    | 1    | 1    | 1   |
| \<14.5mcg/dL             |       | (4)  | (6)  | (3)  | (2)  | (3) |
+--------------------------+-------+------+------+------+------+-----+
| Post-stim change         | 1 (1) | 3    | 2    | 0    | 1    | 1   |
| \<5.6mcg/dL and\         |       | (3)  | (4)  |      | (2)  | (3) |
| post-stim cortisol       |       |      |      |      |      |     |
| \<14.5mcg/dL             |       |      |      |      |      |     |
+--------------------------+-------+------+------+------+------+-----+
| **Endpoint**             |       |      |      |      |      |     |
+--------------------------+-------+------+------+------+------+-----+
| n with cortisols         | 63    | 65   | 26   | 37   | 32   | 36  |
+--------------------------+-------+------+------+------+------+-----+
| AM cortisol \<4mcg/dL    | 2 (3) | 1    | 0    | 1    | 1    | 0   |
|                          |       | (2)  |      | (3)  | (3)  |     |
+--------------------------+-------+------+------+------+------+-----+
| Post-stim change         | 5 (8) | 6    | 4    | 6    | 3    | 6   |
| \<5.6mcg/dL              |       | (9)  | (15) | (16) | (9)  | (   |
|                          |       |      |      |      |      | 17) |
+--------------------------+-------+------+------+------+------+-----+
| Post-stim cortisol       | 4 (6) | 3    | 3    | 2    | 1    | 2   |
| \<14.5mcg/dL             |       | (5)  | (12) | (5)  | (3)  | (6) |
+--------------------------+-------+------+------+------+------+-----+
| Post-stim change         | 3 (5) | 2    | 3    | 1    | 0    | 1   |
| \<5.6mcg/dL and\         |       | (3)  | (12) | (3)  |      | (3) |
| post-stim cortisol       |       |      |      |      |      |     |
| \<14.5mcg/dL             |       |      |      |      |      |     |
+--------------------------+-------+------+------+------+------+-----+
| Note: post-stim =        |       |      |      |      |      |     |
| post-stimulation; AM =   |       |      |      |      |      |     |
| morning                  |       |      |      |      |      |     |
|                          |       |      |      |      |      |     |
| The Day 1 and Endpoint   |       |      |      |      |      |     |
| 'n' includes subjects    |       |      |      |      |      |     |
| with pre or              |       |      |      |      |      |     |
| post-stimulation         |       |      |      |      |      |     |
| cortisol \<0.5mcg/dL;    |       |      |      |      |      |     |
| Endpoint is either Week  |       |      |      |      |      |     |
| 24 or Discontinuation    |       |      |      |      |      |     |
+--------------------------+-------+------+------+------+------+-----+

### Safety in Population Subgroups

The safety profile of SAL, FP, FSC **DISKUS** in the population
subgroups of gender, age, ethnic origin and smoking status were
evaluated in the NDA. The age subgroups were \<65, ≥65, and ≥75 years of
age. The ethnic origin subgroups were White, Black and Other. The
smoking status subgroups were former and current smokers. Former smokers
were defined as subjects with [\>]{.underline}20 pack-year history of
cigarette smoking but discontinued cigarette smoking for at least six
months prior to screening and current smokers were defined as subjects
with [\>]{.underline}20 pack-year history of cigarette smoking and
continued to smoke at screening. Adverse event data was examined for
potential drug-drug interactions in the subgroups using **VENTOLIN**
([\>]{.underline}6 puffs per day) and methylxanthines.

No clinically relevant treatment related differences were observed in
the safety profile when examined by these subgroups. In addition, the
concomitant use of **VENTOLIN** (≥6 puffs per day) or methylxanthines
had no apparent effect on the AE profiles of the FSC 500/50, FSC 250/50,
SAL 50, FP 500, or FP 250 treatment groups.

## Summary of Safety from Clinical Trials

The following conclusion points summarize the clinical safety data from
the three controlled clinical studies (SFCA3006, SFCA3007, and
FLTA3025).

***Extent of Exposure***

-   A total of 2054 COPD subjects were randomized to treatment in the
    three US controlled clinical studies and received at least one dose
    of study medication.

-   The mean extent of exposure was higher for the active drug treatment
    groups compared with the placebo group.

***Adverse Events (AEs)***

-   There was no evidence that the AE profile of either SAL or FP
    changed when the two drugs were used in combination.

-   The overall incidence of AEs was comparable across the treatment
    groups.

-   The most commonly reported AEs, including upper respiratory tract
    infection (URTI), headache, and musculoskeletal pain, were noted in
    similar proportions of subjects across the six treatment groups.
    Throat irritation, candidiasis, and hoarseness/dysphonia, all
    well-documented side effects of inhaled corticosteroids, occurred
    with a higher incidence in the FP and/or FSC groups as compared with
    the placebo or SAL 50 groups.

***AEs Leading to Withdrawal***

-   AEs leading to withdrawal were reported by a relatively small
    proportion of subjects across the treatment groups. Lower
    respiratory events (mainly COPD exacerbation) were the most common
    AEs leading to withdrawal.

***Deaths and Serious Adverse Events***

-   In the controlled clinical studies, four subjects in the placebo
    group died; no deaths occurred in the active drug treatment groups.
    None of the deaths were considered by the investigator to be related
    to study drug.

-   The incidence of SAEs was low and similar across the treatment
    groups. As would be expected in subjects with COPD, SAEs mainly
    included lower respiratory events (e.g., COPD exacerbation,
    pneumonia, and chest symptoms). Only one subject experienced a SAE
    during treatment that was considered by the investigator to be
    related to treatment (angina in SFCA3006 Subject 9060 in the SAL 50
    group); this event was also possibly attributed to a history of
    cardiovascular disease.

***Clinical Laboratory Test Results***

-   There were no clinically relevant treatment effects observed on
    clinical laboratory test results.

***HPA Axis Effects***

-   In SFCA3006 and SFCA3007 morning plasma cortisol concentration and
    short ACTH stimulation texts were performed in a subset of subjects
    at Baseline and the end of treatment. A few subjects had
    abnormalities in short ACTH stimulation test results at Baseline or
    Endpoint with no consistent or dose-related differences observed
    across the treatment groups.

***Cardiovascular Safety***

-   ECGs were recorded for all subjects during the three trials. Few
    subjects (29 of 2054, or 1%) had clinically significant changes in
    ECG results. Overall, the incidence of clinically significant
    abnormalities was lower for those treated with SAL (1%; seven of 688
    subjects who received either SAL 50 or FSC 500/50; no clinically
    significant abnormalities were noted for subjects treated with FSC
    250/50) compared with placebo (3%; 16 of 576 subjects).

-   There was no evidence that administration of SAL or FP alone or in
    combination increased the incidence of QTc prolongation.

-   Holter monitoring was conducted in 158 subjects at Baseline and
    following 1 month of treatment in SCFA3006. The incidence of
    ventricular and supraventricular ectopic events and cardiac rates in
    the placebo group was similar to the active drug treatment groups at
    Screening and at Week 4. Only five subjects experienced a
    significant change from their Screening Holter at Week 4 (one
    subject in the placebo group, one subject in the SAL 50 group, two
    subjects in the FP 500 group, and one subject in the FSC 500/50
    group).

***Vital Signs***

-   No effect of treatment was observed for pulse or blood pressure.

# Bone Mineral Density

The potential impact of inhaled corticosteroids on bone mineral density
(BMD) remains a concern with long-term use. Numerous clinical studies
have examined the effects of inhaled corticosteroids on BMD in subjects
with asthma; however, the following sections will attempt to clarify the
effect of fluticasone propionate on BMD as this is the drug under
review.

## Introduction and Background

In the adult skeleton, bone is composed of a dense outer layer of
cortical bone surrounding a spongy latticework of trabecular bone. It is
this trabecular component of bone, which is the most metabolically
active. Although the entire skeleton loses bone mass with age, the
distribution of bone loss is not uniform because of the different
proportions of trabecular and cortical bone in the various parts of the
skeleton (Erlichman, 1996). As a result, systemic corticosteroids appear
to have a more prominent effect on bones with a high trabecular bone
content. In a study assessing bone mineral density in subjects who had
received oral corticosteroid therapy (cumulative dose up to 60 grams in
less than 20 years), the greatest losses were measured in the trabecular
rich lumbar spine, followed by the femoral neck (a mixture of trabecular
and cortical bone), and finally the predominately cortical femoral shaft
reporting the least amount of bone loss (Erlichman, 1996).

Because there is a well-established relationship between low bone
mineral density and fracture (Black, 1992; Cummings, 1993; Hui, 1989),
many prospective clinical drug trials have utilized bone density
technology to determine treatment effects of active drug. Currently,
dual energy x-ray absorptiometry (DEXA) is the favored method of
detecting changes in bone mineral density given its advantages of low
radiation exposure and measurement accuracy. The ideal site for such
measurement has been traditionally the lumbar spine due to its high
content of metabolically active trabecular bone and its propensity for
fractures (Jones, 1987). The most common type of corticosteroid-induced
fracture occurs at the vertebra (Sambrook, 2000; Van Staa, 2000).

Studies evaluating systemic corticosteroids have reported significant
bone loss with prolonged exposure and suggest an oral prednisone dose of
[\>]{.underline}7.5mg per day at which significant bone loss is observed
(Erlichman, 1996; Goldstein 1999; Adachi, 2000). These effects can often
be seen as rapidly as the first 6 to 12 months after initiating therapy
with decreases in bone mineral density of approximately 5% observed
after 12 months (Adachi, 2000). However, some recovery of bone loss may
be observed in the spine when doses of prednisone are reduced below
7.5mg per day and fracture risk quickly wanes following withdrawal of
corticosteroid therapy (Adachi, 2000; Van Staa, 2000).

## Inhaled Corticosteroids and BMD in patients with COPD

Although systemic exposure due to inhaled corticosteroids is much less
than with oral corticosteroids, the potential for an effect on bone
mineral density has been suggested. However, in adult subjects with
COPD, the few studies examining the association between inhaled
corticosteroids and bone mineral density have given conflicting results.
Currently, there are two completed long-term prospective studies
reported in the literature:

The Lung Health Study II (LHS II; The Lung Health Group, 2000) was a
3-year study designed to evaluate the long-term use of inhaled
triamcinolone 600mcg BID (12 inhalations/day) versus placebo in 1116
COPD subjects aged 40 to 69 (FEV~1~ 30 to 90% predicted; subjects either
current smokers or smokers who had quit within the past 2 years). In a
subset of 412 subjects in this study, bone mineral density measurements
demonstrated a small but statistically significant percent change from
baseline after 36 months of inhaled triamcinolone therapy as compared to
placebo at the lumbar spine (-0.35% vs. +0.98%) and femoral neck (-2.0%
vs. --0.22%).

The European Respiratory Society Study on COPD (EUROSCOP; Pauwels, 1999)
was a 3-year study designed to evaluate the long-term use of inhaled
budesonide (BUD) 400mcg BID versus placebo in 1277 COPD subjects aged 30
to 65 (FEV~1~ 50 to 100% predicted; all subjects were active smokers).
In a subset of 194 subjects, BMD was measured at the lumbar spine,
femoral neck, Ward's triangle, and trochanter. Contrary to the LHS II
findings, results from EUROSCOP demonstrated that there was no
significant change over time and no significant effect of treatment with
ICS on BMD, except for a small but significant difference at the femoral
trochanter in favor of budesonide use.

There may be several reasons for these differences in BMD results with
inhaled corticosteroids. First, patients with COPD are at risk for BMD
loses due to a number of factors commonly found in this population:
advanced age, smoking history, sedentary lifestyle, dietary
deficiencies, potential hormonal (testosterone or estrogen) deficiencies
and long-term systemic corticosteroid use.

These risk factors may have confounded the association made between
inhaled corticosteroids and bone mineral density in these studies. In
the LHS II, baseline characteristics were not provided for those
patients participating in BMD assessments. Unexpectedly, during the
treatment period of this study, bone mineral density of the lumbar spine
increased in the placebo group but not in the active treatment group
which runs contrary to what is known about the normal disposition of
bone over time.

Even with normal aging, bone loss typically occurs at a rate of 0.5 to
1% per year after approximately 25 to 30 years of age at which peak bone
mineral density is normally attained (Goldstein, 1999). This is
potentially even more dramatic for post-menopausal women, in which bone
loss usually occurs at a rate of 2-3% per year for a few years after
menopause and then approximately 1% per year thereafter (Fuleihan,
1995). For that reason, the increase in bone mineral density in the
placebo group is unexpected and may therefore be the result of
imbalances in demographic confounders. Likewise, those small decrements
in bone mineral density observed with triamcinolone over 3 years of
therapy may be the result of normal age-related bone loss (i.e. a 1.5 to
3.0% decline in BMD after 3 years).

Another reason for these observed differences on BMD may lie in the fact
that not all inhaled corticosteroids are the same. Triamcinolone, for
example, has a higher oral bioavailability than fluticasone propionate
(Derendorf, 1997). This may cause triamcinolone to have more of an
impact on bone metabolism, thus having more of an effect on BMD.

Additionally, it is important to place BMD values into clinical
perspective. The reason for assessing BMD is to predict fractures, and
current evidence indicates that the use of inhaled corticosteroids is
unlikely to result in an increase in the incidence of fractures in
patients with COPD. In EUROSCOP, no difference in fracture rate was
noted between active treatment and placebo. In another 3-year study of
751 subjects with COPD aged 40 to 75 (FEV~1~ 50% predicted), a lower
incidence of fractures was reported with FP 500mcg BID (2.4%) compared
with placebo (4.6%) (Burge, 2000).

In a retrospective cohort study conducted using a large UK primary care
database (the General Practice Research Database \[GPRD\]), use of
inhaled corticosteroids in patients with predominately asthma and/or
COPD did not increase the risk of vertebral or non-vertebral fractures
compared with a group of bronchodilator users (Van Staa, 2001). The
study included 170,818 inhaled corticosteroid users, 108,786
bronchodilator only users, and 170,818 control patients. Although the
authors report higher relative risk for fracture in both the inhaled
corticosteroid group and bronchodilator group as compared to the control
group, the excess risk appeared to be related more to the underlying
respiratory disease than to the use of inhaled corticosteroid.

## Inhaled Fluticasone Propionate and BMD

Currently, there are no completed studies of FP evaluating bone mineral
density in patients with COPD. For this reason, BMD is being assessed in
a subset of patients with COPD from the SCO30003 study (also known as
the TORCH study). This is a multi-center, randomized, double-blind,
parallel-group, placebo-controlled study to investigate the long‑term
effects of **ADVAIR DISKUS** 500/50 BID, salmeterol 50mcg BID alone and
fluticasone propionate 500mcg BID alone on survival of patients with
COPD. Approximately 5040 eligible subjects will be randomly assigned to
one of the four double-blind treatments for 156 weeks. The primary
efficacy endpoint is all-cause mortality. Approximately 600 of these
patients with COPD are being prospectively assessed for BMD at the total
hip and L~1~-L~4~ regions of the spine over the 3 years of study drug
treatment.

However, until the results from this study are known, there are
considerable data on BMD with FP treatment in asthma.

Considering that potential effects on BMD with inhaled corticosteroid
treatment are due to systemic absorption, comparison of systemic
exposure information between asthma and COPD may be extrapolated to
assess the relevance of the BMD data available with FP treatment in
asthma to subjects with COPD. Data from several studies that are
reported in Section 2 of this briefing document demonstrate a similar
range of systemic FP exposure between COPD and asthma subjects.
Additionally, considering that the systemic bioavailability of the FP
CFC MDI was shown to be higher than that observed in patients with COPD
treated with **FLOVENT** **DISKUS**, the long-term safety data with the
CFC MDI can be used to conservatively characterize the long-term
systemic safety of **FLOVENT** and **ADVAIR DISKUS** use in patients
with COPD.

The following sections discuss the results of prospective, long-term
studies of fluticasone propionate on bone mineral density in subjects
with asthma to further clarify the relationship of FP and BMD.

### FP versus Placebo

Two long-term studies of FP versus placebo evaluated bone mineral
density over 2 years of treatment in patients aged 18 to 50 with mild to
moderate asthma (FEV~1~ of at least 50% predicted).

Three areas of bone mineral density were measured in each trial: lumbar
spine, proximal femur, and total body. However, definitive conclusions
regarding changes in BMD can only be drawn from changes in the lumbar
spine, the primary safety measure of skeletal effects, since scanning of
the L~1~-L~4~ spine was the only body site that underwent prospective
quality assurance from the osteoporosis central laboratory in these
trials. Results from proximal femur and total body bone mineral density
were collected for observation purposes only, with no prospective
quality assurance of the densitometric measurements.

Both studies demonstrated no significant differences in mean percent
change from baseline in lumbar spine BMD among the treatment groups
studied. Additionally, no significant changes from baseline were
observed between the FP and placebo treatment groups for proximal femur
and total body bone mineral density during either study. The following
summarizes the lumbar spine BMD findings from these studies.

In the FP inhalation aerosol (FP 88mcg and 440 mcg CFC MDI) study (study
FLTA3001, data on file), lumbar spine bone mineral density measurements
demonstrated no statistically significant treatment effects across
treatment groups at any time point (24, 52, 76, and 104 weeks of
double-blind treatment). At Week 104, a mean percent increase from
baseline in bone mineral density was observed in the placebo group
(+0.21%) and FP 88mcg BID group (+0.68%) while a mean percent decrease
from baseline in bone mineral density was observed in the FP 440mcg BID
group (-0.28%). These differences were not statistically significant.

  --------------- ------------ -------------- ---------- -------------- ---------- --------------
  **FP CFC MDI                                                                     
  study** (Study                                                                   
  FLTA3001, data                                                                   
  on file)\                                                                        
  Lumbar spine                                                                     
  bone mineral                                                                     
  density                                                                          
  (g/cm^2^) and                                                                    
  mean change                                                                      
  from baseline ±                                                                  
  SEM                                                                              

  **\             **Placebo\                  **FP 88mcg                **FP       
  Week of Study** (n=54)**                    BID\                      440mcg     
                                              (n=55)**                  BID\       
                                                                        (n=51)**   

                  **N**        **BMD          **N**      **BMD          **N**      **BMD
                               (g/cm^2^)**               (g/cm^2^)**               (g/cm^2^)**

  Screening       54           1.258±0.021    54         1.247±0.018    51         1.218±0.020

  Week 24         49           1.249±0.021    48         1.248±0.020    47         1.220±0.019

  ∆ from baseline              -0.006±0.003              0.002±0.005               -0.002±0.004

  Week 52         44           1.247±0.022    40         1.242±0.023    35         1.215±0.024

  ∆ from baseline              -0.001±0.005              -0.002±0.005              -0.006±0.005

  Week 76         40           1.242±0.022    35         1.243±0.025    27         1.206±0.021

  ∆ from baseline              0.003±0.005               0.002±0.007               0.003±0.006

  Week 104        40           1.240±0.023    32         1.245±0.023    25         1.187±0.023

  ∆ from baseline              0.001±0.005               0.008±0.006               -0.003±0.008

  No significant                                                                   
  differences                                                                      
  were observed                                                                    
  across or                                                                        
  between                                                                          
  treatment                                                                        
  groups                                                                           
  --------------- ------------ -------------- ---------- -------------- ---------- --------------

In the FP inhalation powder (FP 500mcg **ROTADISK**) study (Li, 1999),
bone mineral density measurements demonstrated no statistically
significant treatment effects at the lumbar spine across treatment
groups at any time point (24, 52, 76, and 104 weeks of double-blind
treatment). At Week 104, a mean percent decrease from baseline in bone
mineral density was observed in the placebo group (-0.54%) and in the FP
group (-0.43%).

  ------------- ----------- ------------------ -------------- ---------- ------------- --------------
  **FP ROTADISK                                                                        
  Study** (Li,                                                                         
  1999)\                                                                               
  Lumbar spine                                                                         
  bone mineral                                                                         
  density                                                                              
  (g/cm^2^) and                                                                        
  mean change                                                                          
  from baseline                                                                        
  ± SEM                                                                                

                **Placebo                                     **FP                     
                (n=54)**                                      500mcg BID               
                                                              (n=55)**                 

                **N**       **BMD(g/cm^2^)**   **∆ from       **N**      **BMD         **∆ from
                                               Baseline**                (g/cm^2^)**   Baseline**

  Screening     32          1.251±0.023                       32         1.246±0.025   

  Week 24       28          1.255±0.025        -0.001±0.005   29         1.258±0.028   0.003±0.007

  Week 52       22          1.248±0.028        -0.001±0.006   25         1.239±0.032   -0.003±0.009

  Week 76       19          1.244±0.032        -0.002±0.006   22         1.234±0.034   -0.005±0.009

  Week 104      17          1.229±0.034        -0.007±0.010   21         1.230±0.035   -0.006±0.008

  No                                                                                   
  significant                                                                          
  differences                                                                          
  were observed                                                                        
  across or                                                                            
  between                                                                              
  treatment                                                                            
  groups                                                                               
  ------------- ----------- ------------------ -------------- ---------- ------------- --------------

### FP versus Comparator Inhaled Corticosteroids

Several studies have specifically distinguished the effect of FP on BMD
as compared to other inhaled corticosteroids in patients with asthma.
Three-out-of-three randomized, double-blind trials, which compared FP
and BDP at therapeutically comparable dosages, found significant
differences favoring FP vs. BDP on BMD at doses of FP as high as
1000mcg/day for periods of up to two years (Pauwels, 1998; Egan, 1999;
Medici, 2000). These results suggest that all inhaled corticosteroids
may not have the same propensity to effect BMD and are summarized in the
following table.

+------+------------+-------------+------------------------------------+
| **FP |            |             |                                    |
| CFC  |            |             |                                    |
| MDI  |            |             |                                    |
| ve   |            |             |                                    |
| rsus |            |             |                                    |
| Co   |            |             |                                    |
| mpar |            |             |                                    |
| ator |            |             |                                    |
| Inh  |            |             |                                    |
| aled |            |             |                                    |
| Co   |            |             |                                    |
| rtic |            |             |                                    |
| oste |            |             |                                    |
| roid |            |             |                                    |
| MDIs |            |             |                                    |
| in   |            |             |                                    |
| Pati |            |             |                                    |
| ents |            |             |                                    |
| with |            |             |                                    |
| Asth |            |             |                                    |
| ma** |            |             |                                    |
+------+------------+-------------+------------------------------------+
| **R  | **Study    | **Patient   | **BMD Results**                    |
| ef** | Design**   | Pop.**      |                                    |
+------+------------+-------------+------------------------------------+
| Pauw | R, DB, CO  | 340         | BMD ↑ with FP at all sites.        |
| els, | study\     | moderate to | Differences favoring FP versus BDP |
| 1998 | BDP 500mcg | severe      | at 6 months at the spine (1.0%;    |
|      | or FP      | asthmatics  | p=0.05), femoral neck (1.6%;       |
|      | 250mcg     | previously  | p\<0.01) and Ward's triangle       |
|      | (according | treated     | (3.6%; p=0.01).                    |
|      | to         | with BDP or |                                    |
|      | previously | BUD         |                                    |
|      | taken BDP  | 800-2000    |                                    |
|      | 500mcg or  | mcg/day of  |                                    |
|      | BUD        | which 207   |                                    |
|      | 400mcg)    | were        |                                    |
|      | over 12    | included in |                                    |
|      | months     | the BMD     |                                    |
|      | with study | analysis    |                                    |
|      | cross-over |             |                                    |
|      | after 6    |             |                                    |
|      | months     |             |                                    |
+------+------------+-------------+------------------------------------+
| Hug  | R, OL, PG  | 59 moderate | BMD ↑ in both groups at the lumbar |
| hes, | study\     | to severe   | spine (0.49% FP and 1.59% BUD;     |
| 1999 | FP 500mcg  | asthmatics  | p=0.36) and trochanter (1.77% FP   |
|      | BID versus | previously  | and 2.95% BUD; p=0.36) at 12       |
|      | BUD 800mcg | treated     | months.\                           |
|      | BID over   | with BDP    | BMD ↓ with FP and ↑ with BUD at    |
|      | 12 months  | 1500-2000   | the femoral neck (‑1.61% FP and    |
|      |            | mcg/day or  | 0.15% BUD; p=0.043) at 12 months.  |
|      |            | BUD         |                                    |
|      |            | 1200-1600   | When subjects receiving short      |
|      |            | mcg/day     | courses of oral corticosteroids    |
|      |            |             | during the study were excluded     |
|      |            |             | from analysis there was no         |
|      |            |             | significant difference in BMD at   |
|      |            |             | the femoral neck between tx groups |
|      |            |             | (-0.95% FP, -0.31% BUD; p=0.31).   |
|      |            |             | There were baseline differences    |
|      |            |             | between tx groups: proportion of   |
|      |            |             | women completing study (52% FP and |
|      |            |             | 29% BUD), past oral corticosteroid |
|      |            |             | use (84% FP and 65% BUD) and       |
|      |            |             | baseline predicted PEF (68% FP and |
|      |            |             | 82% BUD)                           |
+------+------------+-------------+------------------------------------+
| E    | R, DB, PG  | 33 moderate | Vertebral trabecular bone did not  |
| gan, | study\     | to severe   | decline with FP but declined with  |
| 1999 | FP 500mcg  | asthmatics  | BDP after 12 months (p=0.006) and  |
|      | BID versus | previously  | 24 months (p=0.004).\              |
|      | BDP        | on BDP or   | Spine and femoral neck BMD         |
|      | 1000mcg    | BUD         | essentially unchanged with FP and  |
|      | BID over   | 1000-2000   | BDP at 12 months (NS) and 24       |
|      | 24 months  | mcg/day for | months (NS).                       |
|      |            | 5 yrs       |                                    |
+------+------------+-------------+------------------------------------+
| Med  | R, DB, PG  | 69 mild to  | No clinically significant loss of  |
| ici, | study\     | moderate    | trabecular or integral (cortical   |
| 2000 | FP         | asthmatics  | and trabecular) bone in the distal |
|      | 400mcg/day | previously  | radius or tibia across tx groups.\ |
|      | versus BDP | on ICS      | BMD ↑ from baseline with FP        |
|      | 800mcg/day | 400-1600    | 400mcg/day and ↓ with BDP          |
|      | over 12    | mcg/day for | 800mcg/day at the lumbar spine     |
|      | months;\   | 6 months    | (p=0.02) after 12 mo.\             |
|      | FP 750     | aged 22 to  | BMD ↑ from baseline with FP        |
|      | mcg/day    | 55; 67%     | 750mcg/day and ↓ with BDP          |
|      | versus BDP | male; all   | 1500mcg/day at the lumbar spine    |
|      | 1          | females     | (NS) after 12 months.              |
|      | 500mcg/day | pr          |                                    |
|      | over 12    | emenopausal |                                    |
|      | months     |             |                                    |
+------+------------+-------------+------------------------------------+
| Harm | FP         | 30          | BMD absolute values of the lumbar  |
| anci | 500mcg/day | non-smoking | spine, femoral neck, trochanter,   |
|      | versus BUD | mild to     | intertrochanter and Ward's         |
| 1999 | 800mcg/day | moderate    | triangle were essentially          |
|      | over 12    | asthmatics  | unchanged with BUD and FP after 12 |
|      | months     | aged 20 to  | months of treatment.               |
|      |            | 55 with no  |                                    |
|      |            | history of  |                                    |
|      |            | chronic     |                                    |
|      |            | systemic    |                                    |
|      |            | cor         |                                    |
|      |            | ticosteroid |                                    |
|      |            | use         |                                    |
+------+------------+-------------+------------------------------------+
| R =  |            |             |                                    |
| Ran  |            |             |                                    |
| domi |            |             |                                    |
| zed; |            |             |                                    |
| DB = |            |             |                                    |
| Do   |            |             |                                    |
| uble |            |             |                                    |
| bl   |            |             |                                    |
| ind; |            |             |                                    |
| OL = |            |             |                                    |
| Open |            |             |                                    |
| la   |            |             |                                    |
| bel; |            |             |                                    |
| PG = |            |             |                                    |
| Para |            |             |                                    |
| llel |            |             |                                    |
| gr   |            |             |                                    |
| oup; |            |             |                                    |
| CO = |            |             |                                    |
| Cro  |            |             |                                    |
| ss-o |            |             |                                    |
| ver; |            |             |                                    |
| Tx = |            |             |                                    |
| Tre  |            |             |                                    |
| atme |            |             |                                    |
| nt;\ |            |             |                                    |
| NS = |            |             |                                    |
| No   |            |             |                                    |
| sig  |            |             |                                    |
| nifi |            |             |                                    |
| cant |            |             |                                    |
| di   |            |             |                                    |
| ffer |            |             |                                    |
| ence |            |             |                                    |
| bet  |            |             |                                    |
| ween |            |             |                                    |
| t    |            |             |                                    |
| reat |            |             |                                    |
| ment |            |             |                                    |
| gro  |            |             |                                    |
| ups; |            |             |                                    |
| ICS  |            |             |                                    |
| =    |            |             |                                    |
| Inh  |            |             |                                    |
| aled |            |             |                                    |
| cort |            |             |                                    |
| icos |            |             |                                    |
| tero |            |             |                                    |
| ids; |            |             |                                    |
| BDP  |            |             |                                    |
| =    |            |             |                                    |
| Be   |            |             |                                    |
| clom |            |             |                                    |
| etha |            |             |                                    |
| sone |            |             |                                    |
| di   |            |             |                                    |
| prop |            |             |                                    |
| iona |            |             |                                    |
| te;\ |            |             |                                    |
| BUD  |            |             |                                    |
| =    |            |             |                                    |
| Bud  |            |             |                                    |
| eson |            |             |                                    |
| ide; |            |             |                                    |
| FP = |            |             |                                    |
| Flu  |            |             |                                    |
| tica |            |             |                                    |
| sone |            |             |                                    |
| pr   |            |             |                                    |
| opio |            |             |                                    |
| nate |            |             |                                    |
+------+------------+-------------+------------------------------------+

## Conclusions

Evaluation of information on BMD with FP therapy provides reassurance
that significant safety issues with the long-term use of FP in patients
with COPD are unlikely and can be summarized as follows:

-   Systemic corticosteroids are known to reduce BMD in areas of bone
    which has a high trabecular bone content such as the lumbar spine
    followed by femoral neck. These are the areas most prone to
    fractures confirming their clinical importance in assessing the
    impact of exogenous corticosteroid therapy.

-   Bone loss following treatment with oral corticosteroids at a dose of
    approximately 7.5mg per day can be seen as early as the first 6
    months of therapy. After 1 year of therapy with oral
    corticosteroids, decreases in bone mineral density of 5% have been
    observed.

-   Although systemic exposure due to inhaled corticosteroids is much
    less than with oral corticosteroids, the potential for an effect on
    bone mineral density has been suggested. Studies examining if
    inhaled corticosteroid in COPD patients impacts BMD have given
    conflicting results. Current evidence indicates that the use of
    inhaled corticosteroids is unlikely to result in an increase in the
    incidence of fractures in patients with COPD.

-   COPD patients have a number of factors which may confound the
    interpretation of BMD results: advanced age, smoking history,
    sedentary lifestyle, dietary deficiencies, potential hormonal
    (testosterone or estrogen) deficiencies, long-term systemic
    corticosteroid use, and/or use of anti-resorptive therapy.
    Imbalances in these variables between treatment groups and/or
    differences between inhaled corticosteroids in their propensity to
    cause systemic effects may explain some of the conflicting findings
    observed with trials evaluating the potential for inhaled
    corticosteroids to influence BMD in patients with COPD.

-   While BMD results with FP treatment in COPD are currently
    unavailable, the similar systemic exposure seen in patients with
    COPD compared to that seen in patients with asthma allows
    extrapolation of the long-term safety data with FP in asthma to
    patients with COPD.

-   No significant effects on BMD were seen in two separate trials
    comparing two years of treatment with FP 500mcg twice daily versus
    placebo in patients with mild asthma.

-   Three-out-of-three randomized, double-blind trials, which compared
    FP and BDP at therapeutically comparable dosages, found significant
    differences favoring FP vs. BDP on BMD at doses of FP as high as
    1000mcg/day for periods of up to two years. These results suggest
    that all inhaled corticosteroids may not have the same propensity to
    effect BMD.

-   These results from asthma are reassuring and suggest that the
    long-term use of **FLOVENT** and **ADVAIR DISKUS** in the treatment
    of patients with COPD is unlikely to be associated with BMD
    reductions. A large ongoing 3-year mortality trial in patients with
    COPD (TORCH, SCO30003) will also evaluate the effects of FP and
    **ADVAIR** on bone mineral density in a subset of patients.

# Discussion of BENEFIT/RISK

## FLOVENT DISKUS

The primary efficacy measure for assessing the clinical effect of
**FLOVENT** treatment in COPD was pre-dose FEV~1~. Improvement in
expiratory airflow has clinical relevance for several reasons. FEV~1~
has been shown to be one of the best predictors of morbidity and
mortality in patients with COPD **(**Postma & Sluiter 1989; ATS, 1995;
Thomason & Strachan, 2000; Hansen, 1999**)**. Additionally, PEF has also
been shown to be a good predictor of overall mortality in COPD (Hansen,
2001**)**. Since corticosteroids do not exert their treatment effects by
direct bronchodilation, an improvement in pulmonary function tests
represents an indirect assessment of treatment effects. The overall
results from three separate clinical trials demonstrated that treatment
with **FLOVENT DISKUS** 250mcg and 500mcg BID was associated with
significant improvements in pre-dose FEV~1~ relative to placebo.

These results, while important, may actually underestimate the true
treatment effects since corticosteroid responsive patients may have been
selectively excluded from enrolling in these trials. Since subjects were
required to discontinue inhaled corticosteroid therapy during the run-in
period, physicians may have been reluctant to enroll subjects who were
benefiting from inhaled corticosteroid therapy into the trials. The
proportion of patients who were using ICS prior to entering these trials
(\~25%) was considerably less than the proportion of patients with COPD
who use ICS estimated from the NDCHealth database (40%) suggesting that
this exclusion criteria may have impacted the types of patients enrolled
in the current trials and caused a bias against FP.

Results from the secondary measures of efficacy support the benefits
seen in FEV~1~ with **FLOVENT DISKUS** treatment across the three
trials. Significant improvements for both doses of **FLOVENT DISKUS**
versus placebo were observed for morning PEF and nighttime awakenings
and generally for daily **VENTOLIN** use and CRDQ. Improvements in
dyspnea were significantly greater with the FP 500 BID dose compared
with placebo. For most clinical measures, the benefits observed with
FP 250 and 500mcg BID were comparable.

Unlike in previous FP trials in COPD (Paggiaro, 1998; Burge, 2000**)**,
the incidence of moderate or severe exacerbation was similar among FP
and placebo treatments. This discrepancy between the current and
previously reported studies may be explained by differences in study
design and treatment duration. In the previous studies, larger numbers
of total exacerbations for both FP and placebo treatment were likely
because subjects were required to have a history of exacerbations and
were also allowed to remain in the study if they experienced an
exacerbation. Subjects in the current studies were not required to have
a history of exacerbations and were discontinued if they experienced one
exacerbation requiring treatment with a corticosteroid or a third
exacerbation requiring treatment with antibiotics. Additionally, the
treatment duration in one of the trials that showed a significant
benefit on exacerbations with FP therapy was three years compared to six
months in the current trials.

It is notable that for treatment with both FP 250 and FP 500 in SFCA3006
and SFCA3007, the improvements in morning pre-dose FEV~1~ were
comparable to that observed for treatment with salmeterol. For most of
the secondary endpoints, the benefits of treatment with FP were also
comparable to that seen with salmeterol. Salmeterol is regarded as one
of the best currently approved treatments for COPD because of it's
favorable benefit/risk/convenience profile. Since FP compared favorably
with salmeterol, these findings suggest that the benefits seen with FP
treatment are also clinically important.

With the exception of expected topical side effects, the safety profile
for patients with COPD treated with FP was comparable to that for
patients treated with PLA and was consistent with findings for asthma
patients. There were no unexpected or exceptional safety considerations
related to the use of FP DISKUS in patients with COPD who participated
in the current studies. Results of HPA axis assessments also support the
safety of FP treatment in COPD. Treatment with FP 250 and 500 BID was
associated with 10% and 20% lower 12-hour cortisol profiles compared to
placebo, respectively. Since the HPA axis is extremely sensitive to the
presence of exogenous corticosteroids, perturbation of plasma cortisol
of this magnitude is considered to be clinically inconsequential. The
lack of differences in the ACTH stimulation test results between FP and
placebo treatment is consistent with an absence of clinically
significant HPA axis suppression.

Although systemic exposure for inhaled corticosteroids is much less than
with oral corticosteroids, the potential for an effect on bone mineral
density (BMD) has been suggested. Recently, the results from a 3-year
study of inhaled triamcinolone \[600mcg BID\] in patients with COPD
suggested that BMD declined with long term use of ICS (Lung Health Study
Group, 2000). However, it is important to recognize that not all inhaled
corticosteroids are the same and that effects observed for treatment
with triamcinolone may not be applicable to treatment with other inhaled
corticosteroids. For example, in the EUROSCOP Study that was similar in
design, treatment with inhaled budesonide \[400mcg BID\] for 3 years did
not affect the BMD of the lumbar spine, femoral neck, or Ward's triangle
**(**Pauwels, 1999**)**. While there are no completed studies that have
examined the effects of FP on BMD in patients with COPD, there are
considerable data on BMD in patients with asthma which are reassuring
(described in Section 7). These studies suggest that not all ICS are
associated with a similar risk of loss of BMD and that FP, at the doses
recommended for COPD, is unlikely to be associated with significant
effects on bone density. The results from a large ongoing 3-year
mortality trial in patients with COPD (TORCH, SCO30003) evaluating the
effects of FP 500 on bone mineral density in a subset of patients should
help to confirm these findings in asthma.

In summary, **FLOVENT DISKUS** 250mcg and 500mcg twice daily provides
clinically important and statistically significant benefits in the
treatment of COPD as assessed by lung function and symptomatic measures.
This benefit was not associated with clinically significant topical or
systemic adverse effects.

## ADVAIR DISKUS

The clinical program for approval of **ADVAIR DISKUS** for treatment of
COPD was developed in collaboration with the FDA and fulfilled the
regulatory requirements for combination products. While treatment with
both doses of FP provided clinically important benefits, treatment with
both **ADVAIR DISKUS** 250/50 and **ADVAIR DISKUS** 500/50 was shown to
be significantly superior to its components for both primary measures of
efficacy.

Since salmeterol and fluticasone propionate exert their benefits by
different mechanisms of action, the primary comparison for assessing the
efficacy of FSC compared with SAL was the differences in changes from
Baseline in pre-dose FEV~1~, while the primary comparison for assessing
the efficacy of FSC compared with FP was the differences in changes from
Baseline in 2-hr post**-**dose FEV~1~. The results from the current
clinical trials demonstrated that treatment with both FSC 250/50 BID and
FSC 500/50 BID provided significantly greater improvements in pre-dose
FEV~1~ compared with both SAL 50 and PLA and significantly greater
improvements in 2-hr post-dose FEV~1~ compared with FP250 and FP500,
respectively, and PLA. The increases in FEV~1~ with both FSC 250/50 and
FSC 500/50 were clinically relevant for treatment of COPD, i.e., 165mL
and 156mL []{.mark}for pre-dose FEV~1~ and 281mL and 261mL for post-dose
FEV~1~, respectively.

Results from the secondary measures of efficacy support the benefits
seen in FEV~1~ with **ADVAIR DISKUS** treatment. Significantly greater
improvements were also observed in morning PEF, as well as TDI, daily
**VENTOLIN** use, CBSQ, nighttime awakenings and CRDQ for treatment with
both FSC 250/50 and FSC 500/50 compared with PLA. Significantly greater
improvements in morning PEF and generally greater improvements in TDI
and CRDQ were observed for treatment with FSC 250/50 or FSC 500/50
compared with FP and SAL. Moreover, while a clinically important
improvement was not always seen with SAL or FP treatment alone,
clinically important improvements were observed for many of the
secondary endpoints when SAL and FP were combined as FSC. These findings
suggest that treatment with both components is needed for control of the
disease for many patients.

Regarding relief of dyspnea, TDI scores for treatment with both FSC
250/50 (score=1.7) and FSC 500/50 (score=2.1) were both substantial and
clinically important, defined as a score ≥1.0 **(**Witek &Mahler, 2001).
The TDI score for treatment with FSC 500/50 and its difference from
placebo (∆=1.7) were substantially greater than that previously observed
in any major clinical trial. Because patients most often modify their
lifestyles to compensate for the dyspnea and activity limitation
associated with reduced expiratory airflow, it is important that
treatment also result in improvements in the patient's quality of life.
It is therefore noteworthy that the mean change from Baseline in Overall
CRDQ scores for treatment with both FSC 250/50 (10.0) and FSC 500/50
(10.0) were clinically important, defined as a change ≥10.0 (Jaeschke,
1989) in addition to being significantly greater than placebo.

The safety profile of FSC 250/50 and FSC 500/50 was consistent with that
observed with the administration of both an inhaled long-acting
beta~2~-agonist plus an inhaled corticosteroid and was not different
from the administration of the individual components alone.
Additionally, no unexpected cardiovascular effects, as assessed by
Holter monitoring and routine ECG, were observed in those patients
receiving FSC compared to that in patients receiving FP 500, SAL 50 or
PLA. Since systemic exposure to salmeterol and fluticasone propionate
administered together has been shown to be similar to that of the
individual agents administered alone, the long-term safety of **ADVAIR
DISKUS** in the treatment of COPD is expected to be similar to the
individual agents. As discussed in Section 7.1, the clinical data
available with fluticasone propionate on BMD is reassuring, and the
ongoing 3-year mortality trial in patients with COPD (TORCH, SCO30003)
will also assess the effects of FSC 500/50 on bone mineral density in a
subset of patients.

In summary, the addition of salmeterol to FP in both **ADVAIR DISKUS**
250/50 and **ADVAIR DISKUS** 500/50 for the treatment of COPD provided
clinically important and statistically significant benefits, as assessed
by lung function and symptomatic measures, superior to that provided by
treatment with FP or SAL alone. These benefits were not associated with
any additional clinically significant topical or systemic adverse
effects.

## Conclusions

The results from the clinical program indicate that both **FLOVENT** and
**ADVAIR** **DISKUS** have a favorable benefit to risk ratio for the
treatment of patients with COPD and can be summarized as follows:

-   The clinical program assessing **FLOVENT** **DISKUS** achieved its
    primary objective of demonstrating statistically significant and
    clinically relevant improvements in the primary measure of efficacy
    (pre-dose FEV~1~) compared with placebo.

-   The magnitude of improvements observed with **FLOVENT** **DISKUS**
    for the primary as well as secondary efficacy measures was
    comparable to that seen with salmeterol which is an approved agent
    for COPD indicating that fluticasone propionate provides clinically
    important benefits in the treatment of patients with COPD.

-   The clinical program also fulfilled the regulatory requirements for
    combination products in the US by achieving significantly greater
    improvements in both of the primary efficacy measures for treatment
    with **ADVAIR DISKUS** 250/50 and **ADVAIR DISKUS** 500/50 compared
    to salmeterol and FP (pre-dose and post-dose FEV~1~, respectively).

-   In addition to improvements in the primary measure of efficacy, both
    **FLOVENT DISKUS** and **ADVAIR DISKUS** provided clinical
    improvements in the secondary efficacy measures compared to placebo.
    Most of these achieved statistical significance for **FLOVENT**
    **DISKUS** and almost all achieved statistical significance for
    **ADVAIR** **DISKUS**.

-   **ADVAIR** **DISKUS** also provided significantly greater
    improvements for several secondary measures of efficacy compared to
    the individual agents (morning PEF and generally greater
    improvements in TDI and CRDQ) and numerical trends for other
    measures of efficacy. These findings suggest that treatment with
    both components is needed for control of the disease for many
    patients.

-   The benefits for treatment with either **FLOVENT DISKUS** or
    **ADVAIR DISKUS** were not associated with any unexpected,
    clinically significant topical or systemic adverse effects.

-   The long-term safety of FP therapy in patients with asthma is
    reassuring and suggests that the use of **FLOVENT** **DISKUS** and
    **ADVAIR** **DISKUS** in COPD is unlikely to be associated with BMD
    reductions.

-   The absence of clinically significant differences in response
    between the two doses suggests that **FLOVENT DISKUS** 250 or
    **ADVAIR DISKUS** 250/50 twice daily serve as the recommended
    starting doses for each medication.

# Appropriate Use of FLOVENT DISKUS and ADVAIR DISKUS in the Management of copd

## Proposed Label: Indications, Dosage and Administration

The wording for the proposed label was chosen as it is similar to the
approved indication wording for other COPD maintenance medications,
including salmeterol, and reflects the effect of inhaled corticosteroids
on aspects of COPD other than bronchoconstriction, and is supported by
results of the clinical programs with **FLOVENT DISKUS**, and **ADVAIR
DISKUS**. As with salmeterol, **FLOVENT DISKUS**, and **ADVAIR DISKUS**
are intended to be used regularly as maintenance therapy for COPD.

Baseline corticosteroid use and disease severity were approximately the
same in all studies, so the clinical program was not designed to define
a starting dose based on these baseline characteristics. Generally, the
two strengths of **FLOVENT DISKUS** and **ADVAIR DISKUS** provided
similar improvements in lung function and most symptom measures.
Therefore, it is recommended that most patients with COPD be started on
the lower dose of **FLOVENT DISKUS** or **ADVAIR DISKUS**. Since better
relief of dyspnea was observed (as measured by the Transition Dyspnea
Index) with the higher dose of **FLOVENT DISKUS** and **ADVAIR DISKUS**,
it may be appropriate to start patients with more severe symptoms on the
higher dose.

### FLOVENT DISKUS

The proposed indication, dosage and administration for **FLOVENT
DISKUS** are as follows:

*"**FLOVENT DISKUS** is indicated for the long‑term, twice‑daily
maintenance treatment of COPD (including emphysema and chronic
bronchitis).*"

*"The starting dosage for adults is 1 inhalation (250 mcg) twice daily.
For patients who do not respond adequately to the starting dose,
increasing the dose to 500 mcg twice daily may provide additional
control."*

### ADVAIR DISKUS

The proposed indication, dosage and administration for **ADVAIR DISKUS**
is as follows:

*"**ADVAIR DISKUS** is indicated for the long‑term, twice‑daily,
maintenance treatment of COPD (including emphysema and chronic
bronchitis)."*

*"The starting dosage for adults is 1 inhalation (250/50 mcg) twice
daily (morning and evening, approximately 12 hours apart). For patients
who do not respond adequately to the starting dose, replacing the
250/50‑strength with the 500/50‑strength may provide additional
control."*

*"The maximum recommended dose is **ADVAIR DISKUS** 500/50 twice daily.
**ADVAIR DISKUS** should be administered twice daily every day. More
frequent administration (more than twice daily) or a higher number of
inhalations (more than 1 inhalation twice daily) of the prescribed
strength of **ADVAIR DISKUS** is not recommended as some patients are
more likely to experience adverse effects with higher doses of
salmeterol."*

### Clinical implications of administration of more than one inhalation of FLOVENT DISKUS or ADVAIR DISKUS

As with patients with asthma, patients with COPD may take more than the
prescribed dose. Although **FLOVENT DISKUS** and **ADVAIR DISKUS**
labeling will specifically warn against using more than one blister
twice daily, it is acknowledged that some patients may, contrary to
recommended use, double the number of inhalations per dose of when they
perceive a deterioration in their condition. This section will address
the clinical implications of administration of double the recommended
salmeterol and FP doses, as well as the results of some pharmacodynamic
studies of **ADVAIR DISKUS**.

#### Effects of salmeterol

Results from seven studies (6 in patients with asthma, and one in
patients with COPD) in a total of 2,608 patients have examined the
safety of administering salmeterol 100mcg BID versus salmeterol 50mcg
BID. In these studies, pharmacologically predictable adverse events were
reported with greater frequency with salmeterol 100mcg BID compared with
50mcg BID, particularly tremor and palpitations. However, these events
were generally mild or moderate and transient in nature and only
occasionally led to withdrawal. No increased incidence of serious
adverse events was observed with salmeterol 100mcg BID as compared to
salmeterol 50mcg BID in these clinical trials.

#### Effects of FP

Clinical data are available to address the safety of FP at doses of
greater than 500mcg twice daily, the highest recommended dose of FP
contained in **ADVAIR DISKUS**. Both **FLOVENT** Inhalation Aerosol and
**FLOVENT** **ROTADISK** are approved for use at doses up to 1000mcg
twice daily (total daily dose 2000mcg), with doses greater than 500mcg
twice daily recommended for use in patients with asthma taking oral
steroids. Effects expected at higher doses of FP include effects known
to occur with higher doses of inhaled corticosteroids, including topical
effects (e.g., candidiasis) and effects on the HPA axis.

#### Effects of ADVAIR DISKUS

No clinical studies have been conducted with **ADVAIR DISKUS** at
greater than the recommended doses. However, safety results from
pharmacodynamic studies in healthy volunteers that used doses of
**ADVAIR DISKUS** greater than the maximum dose showed no significant
clinical effects other than pharmacologically predictable adverse events
for FP and salmeterol that have previously been discussed.

## Summary

The results from this clinical program support the following indication
and recommendations for dosage and administration.

-   **FLOVENT DISKUS** is indicated for the long‑term, twice‑daily
    maintenance treatment of COPD (including emphysema and chronic
    bronchitis). The proposed starting dosage for adults is 1 inhalation
    (250mcg) twice daily. For patients who do not respond adequately to
    the starting dose, increasing the dose to 500mcg twice daily may
    provide additional control.

-   **ADVAIR DISKUS** is indicated for the long‑term, twice‑daily,
    maintenance treatment of COPD (including emphysema and chronic
    bronchitis). The proposed starting dosage for adults is 1 inhalation
    (250/50mcg) twice daily (morning and evening, approximately 12 hours
    apart). For patients who do not respond adequately to the starting
    dose, replacing the 250/50‑strength with the 500/50‑strength may
    provide additional control. The proposed maximum recommended dose of
    **ADVAIR DISKUS** is 500/50mcg twice daily.

Patients who may, contrary to recommended use, double their dose of
**FLOVENT DISKUS** or **ADVAIR DISKUS** to treat worsening symptoms may
experience an increased incidence of pharmacologically predictable
adverse events associated with salmeterol or FP.

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[^7]: ^†^ **FLOVENT** is a Trade Mark of GlaxoSmithKline group of
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[^8]: ^†^ **DISKUS** is a Trade Mark of GlaxoSmithKline group of
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[^9]: ^\*^ **ADVAIR** is a Trade Mark of GlaxoSmithKline group of
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[^13]: Prevalence estimates were derived based on a weighted analysis of
    the National Health And Nutrition Examination Survey III data
    (NHANES-III), a stratified multistage clustered probability survey
    representative of the US population (1988-1994) from the National
    Center for Health Statistics. The data include pulmonary function
    readings for all survey participants aged 45 years and older, as
    well as an interview regarding past and current diagnoses and
    current prescription drugs. The presence of airway obstruction was
    defined as FEV~1~/FVC ratio \<70% (based on GOLD guidelines.)

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[^15]: ^†^ **COMBIVENT** is a Trade Mark of Boehringer Ingelheim.