+-----------------------------------------------------------------------+
| **Backgrounder**                                                      |
|                                                                       |
| **Pulmonary and Allergy Drugs Advisory Committee**                    |
+-----------------------------------------------------------------------+
| **Application Number:** 20-833, SE1-004 **Application Type:** NDA     |
|                                                                       |
| **Sponsor:** GlaxoSmithKline **Proprietary Name:** Flovent® Diskus®   |
|                                                                       |
| **Category of Drug:** Corticosteroid **USAN/Established Name**:       |
| Fluticasone propionate                                                |
|                                                                       |
| **Route of Administration:** Oral inhalation                          |
|                                                                       |
| dry powder                                                            |
|                                                                       |
| **Medical Reviewer:** Charles E. Lee, M.D. **Review Date:** 12/14/01  |
+-----------------------------------------------------------------------+
| **REVIEW SUMMARY:**                                                   |
|                                                                       |
| This is an NDA review for a chronic obstructive pulmonary disease     |
| (COPD) indication for Flovent® Diskus®. The sponsor is                |
| GlaxoSmithKline. The proposed indication is the long-term maintenance |
| treatment of COPD. The proposed starting dose for adults is one       |
| inhalation (250 mcg) twice daily. The labeling allows for increasing  |
| the dose to 2 inhalations (500 mcg) twice daily in patients with an   |
| inadequate response. There were three pivotal studies submitted in    |
| this application, Studies FLTA3025, SCFA3006, and SFCA3007. Although  |
| statistical significance was shown for FP 500, the effect size was    |
| relatively modest, particularly for FLTA3025, where 24 weeks of       |
| treatment resulted in a net improvement in FEV~1~ of only 50 mL.      |
| These studies do not appear to support the efficacy of FP 250 in the  |
| population studied, as a statistically significant difference from    |
| placebo was not noted in replicate studies. Most secondary efficacy   |
| endpoint variables did not support the efficacy of FP 500 or FP 250.  |
| The health-related quality of life instrument does not support the    |
| efficacy of FP 500 or FP 250. The sponsor does not appear to have     |
| established the safety of FP for this indication in the proposed      |
| population. The sponsor has not adequately studied the safety of FP   |
| in non-Caucasian patients with COPD. The pivotal studies were likely  |
| to be of insufficient duration to detect differences between          |
| treatment groups for time and exposure-related events such as         |
| fractures, cataracts, ocular pressure disorders, and disorders of     |
| glucose metabolism. The pivotal studies were not designed to          |
| specifically look for cataracts or systemic bone effects. Safety data |
| from supportive studies raise concerns about a higher incidence of    |
| respiratory infections, pneumonia, HPA axis effects, among others, in |
| FP-treated patients, and do not adequately address bone effects in    |
| the proposed population. The sponsor does not appear to have          |
| sufficiently established that the proposed dose of FP is effective or |
| safe in the treatment of COPD.                                        |
+-----------------------------------------------------------------------+
| **SIGNED:**                                                           |
|                                                                       |
| **Medical Reviewer: Date:**                                           |
|                                                                       |
| **Medical Team Leader: Date:**                                        |
+-----------------------------------------------------------------------+

#  {#section .unnumbered}

# Table of contents {#table-of-contents .unnumbered}

Table of Contents [2](#table-of-contents)

Executive Summary [5](#executive-summary)

1\. Recommendations [5](#recommendations)

2\. Summary of clinical findings [5](#summary-of-clinical-findings)

2.1. Brief overview of clinical program
[5](#brief-overview-of-clinical-program)

2.2. Efficacy [5](#efficacy)

2.3. Safety [7](#safety)

2.4. Dosing [10](#dosing)

2.5. Special populations [10](#special-populations)

Clinical Review [12](#clinical-review)

1\. Introduction and background [12](#introduction-and-background)

1.1. Introduction [12](#introduction)

1.2. Foreign Marketing and Regulatory History
[13](#foreign-marketing-and-regulatory-history)

2\. Clinically relevant findings from chemistry, toxicology,
microbiology, biopharmaceutics, statistics, and/or other consultant
reviews
[14](#clinically-relevant-findings-from-chemistry-toxicology-microbiology-biopharmaceutics-statistics-andor-other-consultant-reviews)

3\. Human pharmacokinetics and pharmacodynamics
[16](#human-pharmacokinetics-and-pharmacodynamics)

3.1. Previously established data [16](#previously-established-data)

3.2. Pharmacokinetic and pharmacodynamic data in this application
[17](#pharmacokinetic-and-pharmacodynamic-data-in-this-application)

3.2.1. FLTA3025 [17](#flta3025)

3.2.2. FMS40243 [18](#fms40243)

3.2.3. FLTA1003 [18](#flta1003)

3.3. Comments from Clinical Pharmacology and Biopharmaceutics review
[19](#comments-from-clinical-pharmacology-and-biopharmaceutics-review)

4\. Description of clinical data and sources
[20](#description-of-clinical-data-and-sources)

5\. Clinical review methods [23](#clinical-review-methods)

5.1. Conduct of the review [23](#conduct-of-the-review)

5.2. Data quality [24](#data-quality)

5.2.1. Ethical standards and financial disclosure
[25](#ethical-standards-and-financial-disclosure)

6\. Integrated review of efficacy [27](#integrated-review-of-efficacy)

6.1. Summary and conclusions [27](#summary-and-conclusions)

6.2. Content [29](#content)

6.3. Description of pivotal studies
[29](#description-of-pivotal-studies)

6.3.1. Primary efficacy endpoint [30](#primary-efficacy-endpoint)

6.3.2. Secondary efficacy endpoints [30](#secondary-efficacy-endpoints)

6.3.3. Disposition, demographics, and baseline characteristics
[31](#disposition-demographics-and-baseline-characteristics)

6.3.4. Primary efficacy endpoint [35](#primary-efficacy-endpoint-1)

6.3.5. Secondary efficacy endpoints
[37](#secondary-efficacy-endpoints-1)

6.3.6. COPD exacerbations [39](#copd-exacerbations)

6.3.7. Health-related quality of life instrument
[41](#health-related-quality-of-life-instrument)

6.4. Subgroup analyses, smoking status and reversibility
[42](#subgroup-analyses-smoking-status-and-reversibility)

6.4.1. Smoking status, subgroup analysis
[42](#smoking-status-subgroup-analysis)

6.4.2. "Non-reversible" population, subgroup analysis
[43](#non-reversible-population-subgroup-analysis)

6.5. Subgroup analyses, demographics
[45](#subgroup-analyses-demographics)

6.6. References [46](#references)

7\. Integrated review of safety [47](#integrated-review-of-safety)

7.1. Summary and conclusions [47](#summary-and-conclusions-1)

7.1.1. Content [50](#content-1)

7.1.2. Safety data from pivotal studies
[50](#safety-data-from-pivotal-studies)

7.1.3. Description of pivotal studies
[50](#description-of-pivotal-studies-1)

7.1.4. Subgroup analyses of safety endpoints in pivotal studies
[65](#subgroup-analyses-of-safety-endpoints-in-pivotal-studies)

7.1.5. Supportive safety data from other studies
[67](#supportive-safety-data-from-other-studies)

7.1.6. Spontaneous postmarketing reports
[79](#spontaneous-postmarketing-reports)

7.1.7. Safety update [79](#safety-update)

7.1.8. References [79](#references-1)

8\. Dosing, regimen, and administration issues
[80](#dosing-regimen-and-administration-issues)

9\. Use in special populations [80](#use-in-special-populations)

9.1. Efficacy in special populations
[80](#efficacy-in-special-populations)

9.1.1. Analysis of efficacy by gender
[81](#analysis-of-efficacy-by-gender)

9.1.2. Analysis of efficacy by age [81](#analysis-of-efficacy-by-age)

9.1.3. Analysis of efficacy by race [81](#analysis-of-efficacy-by-race)

9.2. Safety in special populations [81](#safety-in-special-populations)

9.2.1. Analysis of safety by gender [82](#analysis-of-safety-by-gender)

9.2.2. Analysis of safety by age [82](#analysis-of-safety-by-age)

9.2.3. Analysis of safety by race [83](#analysis-of-safety-by-race)

10\. Conclusions and recommendations
[83](#conclusions-and-recommendations)

11\. APPENDIX: Clinical Studies [86](#appendix-clinical-studies)

11.1. FLTA3025: A randomized, double-blind, parallel-group, comparative
trial of inhaled fluticasone propionate 250 mcg BID, 500 mcg BID, and
placebo BID via the Diskus in subjects with chronic obstructive
pulmonary disease (COPD)
[86](#flta3025-a-randomized-double-blind-parallel-group-comparative-trial-of-inhaled-fluticasone-propionate-250-mcg-bid-500-mcg-bid-and-placebo-bid-via-the-diskus-in-subjects-with-chronic-obstructive-pulmonary-disease-copd)

11.1.1. Summary and reviewer\'s conclusion of study results
[86](#summary-and-reviewers-conclusion-of-study-results)

11.1.2. Study design [88](#study-design)

11.1.3. Objectives [88](#objectives)

11.1.4. Inclusion criteria [89](#inclusion-criteria)

11.1.5. Exclusion criteria [91](#exclusion-criteria)

11.1.6. Protocol amendments [93](#protocol-amendments)

11.1.7. Study procedures [93](#study-procedures)

11.1.8. Allowable concurrent medications
[97](#allowable-concurrent-medications)

11.1.9. Prohibited medications [97](#prohibited-medications)

11.1.10. Drug product and placebo [97](#drug-product-and-placebo)

11.1.11. Assessment of compliance [98](#assessment-of-compliance)

11.1.12. Assessment of signs and symptoms
[98](#assessment-of-signs-and-symptoms)

11.1.13. Health-related quality of life instrument
[100](#health-related-quality-of-life-instrument-1)

11.1.14. Efficacy variables [101](#efficacy-variables)

11.1.15. Pharmacokinetics and pharmacodynamics
[102](#pharmacokinetics-and-pharmacodynamics)

11.1.16. Safety variables [102](#safety-variables)

11.1.17. Statistical considerations [102](#statistical-considerations)

11.1.18. Results [104](#results)

11.1.19. References [132](#references-2)

11.2. SFCA3006: A randomized, double-blind, parallel-group trial of
evaluating the safety and efficacy of the Diskus formulations of
Salmeterol 50 mcg BID and fluticasone propionate 500 mcg BID
individually and in combination as compared to placebo in COPD subjects
[133](#sfca3006-a-randomized-double-blind-parallel-group-trial-of-evaluating-the-safety-and-efficacy-of-the-diskus-formulations-of-salmeterol-50-mcg-bid-and-fluticasone-propionate-500-mcg-bid-individually-and-in-combination-as-compared-to-placebo-in-copd-subjects)

11.2.1. Summary and reviewer\'s conclusion of study results
[133](#summary-and-reviewers-conclusion-of-study-results-1)

11.2.2. Study design [135](#study-design-1)

11.2.3. Objectives [135](#objectives-1)

11.2.4. Inclusion criteria [136](#inclusion-criteria-1)

11.2.5. Exclusion criteria [138](#exclusion-criteria-1)

11.2.6. Protocol amendments [140](#protocol-amendments-1)

11.2.7. Study procedures [140](#study-procedures-1)

11.2.8. Allowable concurrent medications
[144](#allowable-concurrent-medications-1)

11.2.9. Prohibited medications [144](#prohibited-medications-1)

11.2.10. Drug product and placebo [144](#drug-product-and-placebo-1)

11.2.11. Assessment of compliance [145](#assessment-of-compliance-1)

11.2.12. Assessment of signs and symptoms
[145](#assessment-of-signs-and-symptoms-1)

11.2.13. Health-related quality of life instrument
[147](#health-related-quality-of-life-instrument-3)

11.2.14. Efficacy variables [148](#efficacy-variables-1)

11.2.15. Safety variables [149](#safety-variables-1)

11.2.16. Statistical considerations [150](#statistical-considerations-1)

11.2.17. Results [151](#results-1)

11.2.18. References [183](#references-3)

11.3. SFCA3007: A randomized, double-blind, parallel-group trial of
evaluating the safety and efficacy of the Diskus formulations of
Salmeterol 50 mcg BID and fluticasone propionate 250 mcg BID
individually and in combination as compared to placebo in COPD subjects
[185](#sfca3007-a-randomized-double-blind-parallel-group-trial-of-evaluating-the-safety-and-efficacy-of-the-diskus-formulations-of-salmeterol-50-mcg-bid-and-fluticasone-propionate-250-mcg-bid-individually-and-in-combination-as-compared-to-placebo-in-copd-subjects)

11.3.1. Summary and reviewer\'s conclusion of study results
[185](#summary-and-reviewers-conclusion-of-study-results-2)

11.3.2. Study design [187](#study-design-2)

11.3.3. Objectives [187](#objectives-2)

11.3.4. Inclusion criteria [188](#inclusion-criteria-2)

11.3.5. Exclusion criteria [190](#exclusion-criteria-2)

11.3.6. Protocol amendments [192](#protocol-amendments-2)

11.3.7. Study procedures [192](#study-procedures-2)

11.3.8. Allowable concurrent medications
[196](#allowable-concurrent-medications-2)

11.3.9. Prohibited medications [196](#prohibited-medications-2)

11.3.10. Drug product and placebo [196](#drug-product-and-placebo-2)

11.3.11. Assessment of compliance [197](#assessment-of-compliance-2)

11.3.12. Assessment of signs and symptoms
[197](#assessment-of-signs-and-symptoms-2)

11.3.13. Health-related quality of life instrument
[199](#health-related-quality-of-life-instrument-5)

11.3.14. Efficacy variables [200](#efficacy-variables-2)

11.3.15. Safety variables [201](#safety-variables-2)

11.3.16. Statistical considerations [202](#statistical-considerations-2)

11.3.17. Results [203](#results-2)

11.3.18. References [235](#references-4)

#   {#section-1 .unnumbered}

# Executive summary

# Recommendations

Recommendations will be added after the Pulmonary and Allergy Advisory
Committee meeting, which is scheduled for January 17, 2002.

# Summary of clinical findings

## Brief overview of clinical program

Fluticasone propionate is approved in the form of a dry powder inhaler
as Flovent® Rotadisk, NDA 20-549, November 7, 1997, and as Flovent®
Diskus®, NDA 20-833, September 29, 2000. The dry powder inhaler products
are approved for use in adults and children ages 4 years and older for
the maintenance treatment of asthma as prophylactic therapy. Fluticasone
propionate inhalation aerosol (Flovent^®^, NDA 20-548) was approved
March 27, 1996 in three dosage strengths (44 mcg, 110 mcg, and 220 mcg)
for the maintenance treatment of asthma as prophylactic therapy.

The sponsor, GlaxoSmithKline, has submitted this NDA supplement for a
chronic obstructive pulmonary disease (COPD) indication for Flovent®
Diskus®. The proposed indication is the long-term maintenance treatment
of COPD. The proposed starting dose for adults is one inhalation (250
mcg) twice daily. The proposed labeling allows for increasing the dose
to 2 inhalations (500 mcg) twice daily to provide additional control for
patients who do not respond adequately to the starting dose. The
clinical program was also designed to pursue COPD indications for
Serevent Diskus (salmeterol xinafoate 50 mcg) and Advair Diskus
(fluticasone propionate 250 mcg /salmeterol xinafoate 50 mcg and
fluticasone propionate 500 mcg/salmeterol xinafoate 50 mcg). Submissions
similar to the Flovent Diskus NDA supplement have been simultaneously
submitted to the Serevent Diskus NDA (NDA 20-692) and to the Advair
Diskus NDA (NDA 21-077).

This submission refers to three pivotal clinical studies, Studies
FLTA3025, SFCA3006, and SFCA3007. These studies are submitted in support
of the efficacy of FP in the treatment of COPD. The pivotal studies were
randomized, double-blind, parallel group, placebo-controlled,
multicenter studies. Each of the pivotal studies had a 24-week treatment
duration. Study FLTA3025 evaluated the efficacy of FP 250 and FP 500
compared with placebo. SAL 50/FP 500 and FP 500 were compared with each
other and with placebo in SFCA3006. SAL 50/FP 250 and FP 250 were
compared with each other and with placebo in SFCA3007. All three studies
were similar in design, subject entrance criteria, and overall conduct
to provide replication of treatment arms across studies. The sponsor
provided safety data from the pivotal studies, supportive safety data
from other studies, and a safety update, which included postmarketing
reports and a literature review, in support of the safety of FP in the
treatment of COPD.

## Efficacy

The primary efficacy variable for the evaluation of FP in the pivotal
studies was the pre-dose FEV~1~. The primary analysis for FP was the
comparison of the mean morning pre-dose FEV~1~ between treatment groups
at endpoint. Comparisons of FP 500 with placebo showed statistically
significant differences in mean change from baseline in pre-dose FEV~1~
in both FLTA3025 and SFCA3006, although the effect size observed in
FLTA3025 was only 50 mL, half of the "clinically significant" 100 mL the
sponsor had powered the study to detect. The effect size reported in
SFCA3006 was 113 mL. Comparisons of FP 250 with placebo showed
statistically significant differences in mean change from baseline in
pre-dose FEV~1~ only for SFCA3006 with an effect size of 108 mL, but not
for FLTA3025, which had an effect size of only 27 mL.

No active treatment group had a clinically significant difference from
the placebo group in mean change from baseline in the Global Assessment
Score (GAS) of the Chronic Bronchitis Symptom Questionnaire (CBSQ). FP
500 and FP 250 did not have a clinically significant difference from the
placebo group in the mean Transition Dyspnea Index (TDI) score. In
FLTA3025 there were slightly fewer COPD exacerbations in FP 500 and FP
250 groups than in placebo, with a dose-response effect noted.
Otherwise, the incidence of COPD exacerbations in the three pivotal
studies was fairly similar among treatment groups. The incidence of
moderate or severe COPD exacerbations in the three pivotal studies was
similar among treatment groups. There were no significant differences
between the FP and placebo groups for time to withdrawal from the study,
time to withdrawal due to COPD exacerbation, and time to withdrawal due
to COPD-related condition. Small changes from baseline in AM PEFR, daily
Ventolin use, and number of awakenings per night requiring Ventolin use
were noted for FP 250 and FP 500 groups.

The Chronic Respiratory Disease Questionnaire (CRDQ) was used to compare
changes in the COPD-related quality of life for treatment groups. No
active treatment group had a clinically significant difference from the
placebo group in mean change from baseline in the Overall score of the
CRDQ.

Subgroup analysis by smoking status showed that former smokers had
larger mean changes from baseline in FEV~1~ at endpoint for all active
study treatments than did current smokers. Subgroup analysis for the
non-reversible and reversible groups showed that the non-reversible
group had smaller mean changes from baseline in FEV~1~ at endpoint for
all active study treatments than did the reversible group.

These studies do not appear to sufficiently support the efficacy of FP
500 or FP 250 in the treatment of COPD. The main issues included the
patient population studied, inconsistent findings in the three pivotal
studies with the primary endpoint, the absence of strong support from
the secondary endpoints, and the failure of the studies to fully support
the clinical relevance of the primary endpoint, particularly with regard
to the quality of life (QOL) instrument and COPD exacerbation.

With regard to the patient population, the sponsor has not adequately
studied the efficacy of FP in non-Caucasian patients with COPD.
Additional study of the efficacy of FP in a more racially diverse study
population is indicated. There are serious questions about whether the
patient population studied, of which 51% to 59% were highly reversible,
is representative of the US COPD population as a whole, for which a
broad indication is sought. Although statistical significance was shown
for FP 500, the effect size was relatively modest, particularly for
FLTA3025, where 24 weeks of treatment resulted in a net improvement in
FEV~1~ of only 50 mL. It should be noted that this result was also
heavily driven by the "reversible" subgroup and by subjects who had
stopped smoking. These studies do not appear to sufficiently support the
efficacy of FP 250 in the population studied, as a statistically
significant difference from placebo was not noted in replicate studies.
In general, most of the secondary efficacy variables did not support the
efficacy of FP 500 or FP 250. Secondary efficacy variables that would be
expected to be correlated to the primary endpoint, such as PEFR, showed
modest treatment effects and therefore do not add substantially to the
argument in favor of efficacy for this product.

The quality of life (QOL) instrument, the CRDQ, does not appear to
support the efficacy of FP 500 or FP 250. This is particularly
concerning because all three of the pivotal studies had evaluation of
QOL as one of their primary objectives. This was included because
relatively short-term (6 months) changes in FEV~1~ have uncertain
clinical significance and do not have the same correlation with
mortality that long-term (3 year) changes would have. The small effect
size in FEV~1~ combined with the observation that the patients
experienced no detectable benefit vs. placebo in a well-validated QOL
instrument argues strongly against a conclusion of efficacy for FP for
the COPD indication.

## Safety

Safety data from the three pivotal studies in this application were
integrated in support of this application. Adverse events (AEs) were
fairly common in these studies. A dose response effect was noted when
comparing all AEs for placebo (69%) with FP 250 (74%) and FP 500 (80%).
AEs occurring at a frequency ≥3% and more frequently with FP 250, FP
500, SAL 50/FP 250, or SAL 50/FP 500 than with placebo included upper
respiratory tract infection, headaches, musculoskeletal pain, throat
irritation, viral respiratory infections, URI, candidiasis of the mouth
or throat, nasal congestion/blockage, cough, sinusitis, nausea and
vomiting, hoarseness/dysphonia, fever, malaise and fatigue, muscle
cramps and spasms, rhinitis, dizziness, hypertension, sinusitis/sinus
infection, and muscle pain.

When comparing placebo with FP 250 and FP 500, a dose response effect
was noted for URTI, headaches, viral respiratory infections, URTI,
candidiasis of the mouth or throat, nasal congestion/blockage, and
muscle pain. Many of the AEs noted are also noted in the labels for
Flovent MDI and Flovent Rotadisk. AEs reported in these studies that are
not noted in current labeling for other Flovent products include
musculoskeletal pain, nausea and vomiting, airway irritation (throat
irritation, cough, rhinitis), dizziness, malaise and fatigue.
Differences could be attributed to differences in patient population or
in the magnitude of the dose of FP, which was high for COPD (500 mcg to
1000 mcg per day) when compared to the asthmatic population (100 mcg to
up to 500 mcg per day for moderate persistent asthma; 500 mcg to 1000
mcg per day for the oral corticosteroid sparing indication).

AEs associated with use of inhaled and systemic corticosteroids were
noted in these studies. Candidiasis, throat irritation, and
hoarseness/dysphonia were more common in FP 250, FP 500, SAL 50/FP 250,
and SAL 50/FP 500 than in placebo. A dose response effect for
candidiasis was seen when comparing placebo (1%) with FP 250 (7%) and FP
500 (13%). There were a small number of AEs for fractures, cataracts,
hyperglycemia, diabetes mellitus, and impaired glucose tolerance, and
the frequencies of these AEs were similar among treatment groups. There
was a higher frequency of pneumonia for FP 250 (1%), FP 500 (2%), and
SAL 50/FP 500 (1%) than for placebo (\<1%). There were four deaths in
placebo-treated patients in these studies. There were no deaths in
patients that received active treatment. There was a higher frequency of
SAEs due to COPD for FP 250 and FP 500, and a suggestion of an
association with SAEs due to pneumonia with FP treatment. Withdrawals
due to any AE were more common in FP 500 and SAL 50/FP 500 than in
placebo. Withdrawals due to AEs for COPD were more common in FP 500 and
FP 250 than in placebo; dose response effect was noted. Withdrawals due
to pneumonia were more common in FP 500, FP 250, and SAL 50/FP 500 than
for placebo. Withdrawals due to candidiasis mouth/throat only occurred
in FP 500-treated patients.

Plasma cortisol levels were studied in FLTA3025. FP treatment groups had
lower mean cortisol AUC~12~ and mean C~min~ than the placebo group, with
a dose response effect noted. Mean cortisol AUC~12~ was 21% lower than
placebo for FP 500 and 10% lower than placebo for FP 250, indicating
dose-related systemic absorption and systemic activity from Flovent
Diskus. The plasma cortisol samples were taken at Week 4, early in the
study. Cosyntropin stimulation testing was performed in SFCA3006 and
SFCA3007 on a subset of patients (15% to 20%). The data for cosyntropin
stimulation testing show no evidence of adrenal suppression, however,
cosyntropin stimulation testing is intended as a means to diagnose
adrenal insufficiency and is a relatively insensitive measure of adrenal
suppression.

The sponsor also provided safety data from other studies to support this
application. These data included blinded listings of deaths and SAEs
from ongoing clinical studies, as well as safety information from
completed clinical pharmacology and clinical studies. Blinded listings
of deaths and SAEs from ongoing clinical studies provided no useful
safety information. Many AEs and SAEs from the completed studies are
similar to those that were noted in the three pivotal studies and those
noted in current labeling of Flovent product formulations. However, both
upper respiratory infections and lower respiratory infections, including
pneumonia, were more frequent in FP-treated patients than in placebo.
Patients treated with FP MDI 500 mcg BID over the 3-year course of
FLIT78 (also known as ISOLDE) had a higher frequency of events
associated with systemic effects of corticosteroids than patients
treated with placebo. These events included gastrointestinal hemorrhage,
diabetes mellitus, hyperglycemia, ocular pressure disorders, decreased
cortisol, abnormal adrenal hormone levels, Cushing's syndrome/symptoms,
hypofunction of the adrenal cortex, skin hemorrhage, acne and
folliculitis, and muscle atrophy, weakness, and tiredness.

These supportive studies also included laboratory data that showed
evidence of HPA-axis effects of inhaled FP. FLTA1003 was a open-label,
single dose, 4-way crossover, PK/PD study in normal subjects. Patients
received 1000 mcg of FP in four different dosage strengths of the Diskus
formulation. Compared to baseline, mean urinary cortisol excretion was
decreased by 42% to 62% in all treatment groups in this study, and many
individual patients had decreases in urinary cortisol excretion even
after the first dose of study treatment.

The sponsor studied effects on bone mineral density in two controlled,
long-term studies of FP in the treatment of asthma. These studies were
FLTA3001 and FLTA3017. Lumbar spine bone mineral density measurements in
FLTA3001 demonstrated no statistically different treatment effects at
24, 52, 76, and 104 weeks of double-blind treatment with placebo, FP MDI
88 mcg BID, or FP MDI 440 mcg BID. Lumbar spine bone mineral density
measurements in FLTA3017 demonstrated no statistically different
treatment effects at 24, 52, 76, and 104 weeks of double-blind treatment
with placebo or FP 500 mcg BID with the Rotadisk formulation. The lumbar
spine was the only area in these studies that underwent prospective
quality assurance from the osteoporosis central laboratory. Results from
the proximal femur had no prospective quality assurance. These studies
were small (N=160 and N=64) and performed in a young population (18 to
40 years) of asthma patients who were primarily male. It is likely that
these studies were underpowered to detect a difference in bone mineral
density. In addition, the asthmatic population may have a different
sensitivity to bone effects of corticosteroids, and have a far smaller
risk of pathological fracture per decrement in bone mineral density than
older COPD patients would have.

The sponsor does not appear to have established the safety of FP in the
proposed population. The sponsor has not adequately studied the safety
of FP in non-Caucasian patients with COPD. Additional study of the
safety of FP in a more racially diverse study population is strongly
suggested. Further study is also required to demonstrate the safety of
this product in the COPD population, a population that would be at
higher risk for systemic corticosteroid effects. The pivotal studies
were likely to be of insufficient duration to detect differences between
treatment groups for dose and duration-related events such as fractures,
cataracts, ocular pressure disorders, and disorders of glucose
metabolism. The pivotal studies were not designed to specifically look
for cataracts or systemic bone effects and exclusion criteria
specifically selected subjects with baseline bone or ocular problems.
Safety data from the supportive studies raise concerns about a higher
incidence of respiratory infections, pneumonia, HPA axis effects, among
others, in FP-treated patients, and do not adequately address bone
effects in the proposed population.

The sponsor has recently started a 3-year study of FP 500 mcg BID, SAL
50/FP 500 BID, SAL 50 BID, and placebo BID via the Diskus formulation in
COPD patients (SCO30003). Bone density is to be evaluated over three
years in a subpopulation of 600 patients. This study will also assess
bone fractures and ocular events in the entire study population of 5000
patients. The long-term safety data that will be provided in this study
will be critical in assessing the long-term risk/benefit analysis for
this product in the proposed population.

## Dosing

The FP Diskus 500 mcg is not an approved product, and the sponsor is not
seeking approval of this product for this indication in this
application. The sponsor's proposed starting dosage for COPD is 1
inhalation (250 mcg) twice daily. The proposed labeling allows for
increasing the dose to 2 inhalations (500 mcg) twice daily to provide
additional control for patients who do not respond adequately to the
starting dose, although no data are provided to support this dose
increase.

The sponsor has argued dose proportionality of the approved FP 250 mcg
and proposed FP 500 mcg Diskus products in another study included in
this submission, FLTA1003. Although still under review by OCPB, it
appears that data from FLTA1003 indicate FP 250 X 2 puffs provides less
active drug than FP 500 X 1 puff. However, in FLTA3025, a multiple dose,
4-week study, FP 250 Diskus appears to be more than dose proportional to
the FP 500 Diskus. Since the latter trial is comprised of the population
of interest, these results are more relevant to the proposed indication.

The primary efficacy endpoint data in the pivotal studies showed a
statistically significant treatment effect for the FP 500 mcg BID when
administered with the FP 500 Diskus. However, the effect was modest and
was offset by the largely negative secondary efficacy endpoint data and
by the lack of effect on health-related quality of life. Furthermore,
most of the secondary efficacy variables and the health-related quality
of life instrument did not support the efficacy of FP 500 mcg BID when
administered with the FP 500 Diskus. The sponsor has not studied the
efficacy or safety of FP 500 mcg BID when administered as 2 inhalations
BID of the FP 250 Diskus. The fact that the FP 250 mcg Diskus may be
more than dose proportional to the FP 500 mcg Diskus does raise
additional safety concerns. The pivotal studies do not appear to support
the efficacy of FP 250 BID when administered with the to-be-marketed FP
250 mcg Diskus product, as a statistically significant difference from
placebo was not noted in replicate studies.

Examination of safety data for the pivotal studies reveals a dose
response effect for FP 500 mcg BID and FP 250 mcg BID for upper
respiratory tract infections (URTI), headaches, viral respiratory
infections, candidiasis of the mouth or throat, nasal
congestion/blockage, and muscle pain.

## Special populations

The under-representation of non-Caucasian patients in this study is a
serious deficiency of these studies. The sponsor has not adequately
studied the efficacy or safety of FP in non-Caucasian patients with
COPD. Additional study of the safety of FP in a more racially diverse
study population is indicated. Efficacy and safety data from future
studies should be examined to determine if the increases in COPD
exacerbations in women and patients ≥ 65 years represent true safety
signals.

The sponsor provided subgroup analyses of efficacy by gender, race, and
age. Males had greater absolute mean changes from baseline in FEV~1~ at
endpoint than women for all active treatment groups. Mean percent change
from baseline in FEV~1~ at endpoint was similar for men and women,
however, indicating the larger absolute mean change in men was due to
larger lung volumes. Women in the FP 500 and FP 250 groups had more
slightly more moderate or severe COPD exacerbations than men, when
compared with data for the placebo group. There was no consistent
association of gender with AEs for any of the treatment groups. There
was no association of gender for the four deaths in the pivotal studies.

Incidences of COPD exacerbations in the FP 500 and FP 250 groups
relative to placebo were higher for patients ≥65 years than those \<65
years. Incidences of COPD exacerbations in the FP 500 group relative to
placebo were higher for patients ≥65 years than those \<65 years.
Pneumonia and withdrawals due to pneumonia appeared to be more common in
patients ≤65 years of age who were treated with FP 500.

As noted in each of the individual study reviews in this document, the
vast majority of patients in this study were of Caucasian race. The
small number of Non-Caucasian patients makes it difficult to draw firm
conclusions. The overall frequency of AEs differed by race. The overall
frequency of AEs in Caucasian patients ranged from 69% (223/321) to 81%
(298/367). The overall frequency of AEs in Black patients ranged from
47% (8/17) to 72% (13/18). The overall frequency of AEs in patients of
Asian or Other race ranged from 33% (1/3) to 43% (3/7). The difference
in frequencies between the races is likely to be a result of the small
sample size of patients of Black and Asian/Other races. The small number
of non-Caucasian patients did not allow for an analysis of SAEs,
withdrawals due to AEs, laboratory results, or ECG results by race.

No patients were studied in the pediatric age group, and therefore there
is no analysis of this subgroup. The sponsor has requested a waiver of
pediatric studies in children 0-16 years of age. The sponsor's
justification for this request for waiver is that COPD, as defined by
the American Thoracic Society, does not occur in this age group
\[pediatricwaiverrequest.pdf, page 1\].

There were no pregnancies reported in the conduct of the pivotal
studies, and therefore there is no analysis of this subgroup.

# Clinical REVIEW {#clinical-review .unnumbered}

# Introduction and background

## Introduction

This is an NDA supplement for a chronic obstructive pulmonary disease
(COPD) indication for Flovent® Diskus®. The sponsor is GlaxoSmithKline.
The proposed indication is the long-term maintenance treatment of COPD.
The proposed starting dose for adults is one inhalation (250 mcg) twice
daily. The proposed labeling allows for increasing the dose to 2
inhalations (500 mcg) twice daily to provide additional control for
patients who do not respond adequately to the starting dose. The
clinical program was also designed to pursue COPD indications for
Serevent Diskus (salmeterol xinafoate 50 mcg) and Advair Diskus
(salmeterol xinafoate 50 mcg/fluticasone propionate 250 mcg and
salmeterol xinafoate 50 mcg/fluticasone propionate 500 mcg). Submissions
similar to the Flovent Diskus NDA supplement have been simultaneously
submitted to the Serevent Diskus NDA (NDA 20-692) and to the Advair
Diskus NDA (NDA 21-077).

COPD is a disease in which airflow obstruction results from chronic
bronchitis and/or emphysema. Symptoms include cough, increased sputum
production, and dyspnea. The disease is characterized by intermittent
acute exacerbations of these symptoms, and by an increase in the rate of
the natural decline in pulmonary function that occurs with age. COPD is
most commonly related to cigarette smoking.

Bronchodilators, both beta agonists and anticholinergics, are important
medications approved for use in treatment of symptoms of COPD. Inhaled
corticosteroids are widely used off-label in the treatment of COPD.
Although inhaled corticosteroids have been clearly demonstrated as safe
and effective in the treatment of asthma, and represent the mainstay of
controller treatment in asthma, their role in COPD treatment is not
clear. Systemic corticosteroids have been demonstrated as effective in
the acute treatment of COPD exacerbations. However, varying degrees of
benefit in the treatment of COPD, from some effect to no effect, have
been noted in the literature.

The sponsor notes that corticosteroids attenuate chemotaxis and
recruitment of neutrophils, which are important effector cells in COPD.
Accordingly, the sponsor believes that the presence of airway
inflammation serves as the primary scientific rationale for the proposed
use of fluticasone propionate in the treatment of COPD \[summary.pdf,
page 4\].

The sponsor also believes there is a role for salmeterol and the
combination of salmeterol and fluticasone propionate in the maintenance
treatment of COPD, and as noted above, has submitted efficacy
supplements to these NDAs as well \[summary.pdf, pages 4-5\].

## Foreign Marketing and Regulatory History

Fluticasone propionate has been approved for the treatment of COPD in
the following countries \[summary.pdf, page 10\]:

Argentina

Austria

Belgium

Colombia

Czech Republic

Germany

Iceland

Ireland

Israel

Latvia

Lithuania

Luxembourg

Netherlands

Peru

Russia

Spain

Applications for fluticasone propionate are pending for the treatment of
COPD in the following countries \[summary.pdf, pages 11-12\]:

\[ \]

\[ \]

\[ \]

\[ \]

\[ \]

Applications for fluticasone propionate for the treatment of COPD have
been withdrawn by the sponsor or rejected by regulatory authorities in
the following countries \[summary.pdf, pages 12-13\]:

\[ \]

\[ \]

\[ \]

\[ \]

\[ \]

> \[ \]

\[ \]

\[ \]

Fluticasone propionate is approved in the form of a dry powder inhaler
as Flovent® Rotadisk (50 mcg, 100 mcg, 250 mcg) NDA 20-549, November 7,
1997, and as Flovent®

Diskus®, (50 mcg, 100 mcg, 250 mcg) NDA 20-833, September 29, 2000. It
should be noted that the Flovent Diskus 500 mcg product, which was used
in pivotal clinical studies FLTA3025 and SFCA3006 in this application,
is not approved in the US. The dry powder inhaler products are approved
for use in adults and children ages 4 years and older for the
maintenance treatment of asthma as prophylactic therapy. Fluticasone
propionate inhalation aerosol (Flovent® NDA 20-548) was approved March
27, 1996 in three dosage strengths (44 mcg, 110 mcg, and 220 mcg) for
the maintenance treatment of asthma as prophylactic therapy.

# Clinically relevant findings from chemistry, toxicology, microbiology, biopharmaceutics, statistics, and/or other consultant reviews

Chemistry, manufacture and controls information for this application was
cross-referenced to NDA 20-833 for Flovent Diskus 50, 100, and 250 mcg
per blister drug product. NDA 20-833 was previously approved for use in
inhalation drug products on September 29, 2000. Flovent Diskus
Inhalation Powder is formulated to contain either 50, 100, or 250 mcg of
fluticasone propionate (micronized) per blister made up to 12.5 mg with
lactose monohydrate \[cmc\\dpcrossreference.pdf, page 1\].

The active component of Flovent Diskus 250 mcg is fluticasone
propionate, a corticosteroid having the chemical name
S-(fluoromethyl)6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate,
17-propionate.

Fluticasone propionate is a white to off-white powder with a molecular
weight of 500.6, and the empirical formula is C~25~H~31~F~3~O~5~S. It is
practically insoluble in water, freely soluble in dimethyl sulfoxide and
dimethylformamide, and slightly soluble in methanol and 95% ethanol.
Flovent Diskus 250 mcg is a specially designed plastic device containing
a double-foil blister strip of a powder formulation of fluticasone
propionate intended for oral inhalation only. Each blister on the
double-foil strip within the device contains 250 mcg of microfine
fluticasone propionate in 12.5 mg of formulation containing lactose.
After a blister containing medication is opened by activating the
device, the medication is dispersed into the airstream created by the
patient inhaling through the mouthpiece \[labeling/current.pdf, page
1\].

The formulation is contained in a sealed double foil blister strip,
which in turn is contained within the Diskus device. Flovent Diskus is
supplied as a disposable two-tone, orange-colored device and is packaged
within an orange-colored plastic-coated foil pouch. Flovent Diskus is
also supplied in a sample and institutional size as a two-tone,
orange-colored disposable Diskus inhalation device containing 28
blisters. Flovent Diskus is manufactured at Glaxo Wellcome Operations,
Ware, United Kingdom. This manufacturing site was previously inspected
and received satisfactory GMP status in conjunction with NDA 21-077 for
Advair Diskus on February 8, 2000 \[cmc\\dpcrossreference.pdf, page 1\].

The sponsor included a statement of categorical exclusion for the
environmental assessment because they estimate that the concentration of
the drug substance active moiety will not be one part per billion or
greater at the point of entry into the aquatic environment
\[cmc\\environ.pdf, page 1\].

The batch numbers of medication that were used in the pivotal studies in
this application are displayed in Table 2.1. The sponsor states that the
formulations of Flovent used in this study were representative of the
commercial product in terms of input materials, scale of manufacture,
manufacturing equipment, and manufacturing process. The only differences
between the batches of Flovent that were supplied for this study and the
commercial product were the device coloration and the overwrap. All
batches of Ventolin nebules and Ventolin MDI used in this study were the
approved commercial product. The placebo used in this study was
identical to the active product used in this study except for the
absence of active drug \[NDA 20-833, SE1-004, 9/17/01, page 3; NDA
20-833, SE1-004, 12/5/01, page 1\].

Table 2.1. Batch numbers of study medication, pivotal clinical studies,
NDA 20-833 S004 \[clinstat\\copd\\flta3025.pdf, page 44;
clinstat\\copd\\scfa3006.pdf, page 56; clinstat\\copd\\scfa3007.pdf,
page 47\].

+-----------------------------------+-----------------------------------+
| **FLTA3025**                      |                                   |
+-----------------------------------+-----------------------------------+
| **Product**                       | **Batch numbers**                 |
+-----------------------------------+-----------------------------------+
| Placebo Diskus                    | WP1WF9                            |
|                                   |                                   |
|                                   | WP25L4                            |
+-----------------------------------+-----------------------------------+
| FP Diskus 250 mcg                 | U98/028A                          |
+-----------------------------------+-----------------------------------+
| FP Diskus 500 mcg                 | U98/024C                          |
+-----------------------------------+-----------------------------------+
| Ventolin MDI, 90 mcg/puff         | 8ZP0692                           |
|                                   |                                   |
|                                   | 8ZP0909                           |
|                                   |                                   |
|                                   | 8ZP1741                           |
|                                   |                                   |
|                                   | 8ZP1924                           |
|                                   |                                   |
|                                   | 8ZP1924                           |
|                                   |                                   |
|                                   | 9ZP0124                           |
+-----------------------------------+-----------------------------------+
| Ventolin nebules, 0.098%, 2.5     | 970963                            |
| mg/3 mL                           |                                   |
|                                   | 980904                            |
|                                   |                                   |
|                                   | 980905                            |
|                                   |                                   |
|                                   | 980911                            |
|                                   |                                   |
|                                   | 980901                            |
+-----------------------------------+-----------------------------------+
| **SCFA3006**                      |                                   |
+-----------------------------------+-----------------------------------+
| **Product**                       | **Batch numbers**                 |
+-----------------------------------+-----------------------------------+
| Placebo Diskus                    | WP25L4                            |
|                                   |                                   |
|                                   | WP31R9                            |
|                                   |                                   |
|                                   | WP2GHW                            |
+-----------------------------------+-----------------------------------+
| FP Diskus 500 mcg                 | U98/024C                          |
+-----------------------------------+-----------------------------------+
| SAL Diskus 50 mcg                 | WP2D8B                            |
|                                   |                                   |
|                                   | WP2NLT                            |
|                                   |                                   |
|                                   | WP2T35                            |
+-----------------------------------+-----------------------------------+
| SAL Diskus 50 mcg/FP Diskus 500   | U97/061C                          |
| mcg                               |                                   |
|                                   | WP2NPB                            |
|                                   |                                   |
|                                   | B003371                           |
+-----------------------------------+-----------------------------------+
| Ventolin MDI, 90 mcg/puff         | 8ZP0909                           |
|                                   |                                   |
|                                   | 9ZP0259                           |
+-----------------------------------+-----------------------------------+
| Ventolin nebules, 0.098%, 2.5     | 980905                            |
| mg/3 mL                           |                                   |
|                                   | 990903                            |
|                                   |                                   |
|                                   | 980901                            |
+-----------------------------------+-----------------------------------+
| Cortrosyn 0.25 mg injection       | 2240697731                        |
|                                   |                                   |
|                                   | 2300199731                        |
|                                   |                                   |
|                                   | 2310299731                        |
+-----------------------------------+-----------------------------------+
| **SFCA3007**                      |                                   |
+-----------------------------------+-----------------------------------+
| **Product**                       | **Batch numbers**                 |
+-----------------------------------+-----------------------------------+
| Placebo Diskus                    | WP25L4                            |
|                                   |                                   |
|                                   | WP31R9                            |
|                                   |                                   |
|                                   | WP2GHW                            |
+-----------------------------------+-----------------------------------+
| FP Diskus 250 mcg                 | U98/028A                          |
|                                   |                                   |
|                                   | B006597                           |
+-----------------------------------+-----------------------------------+
| SAL Diskus 50 mcg                 | WP2D8B                            |
|                                   |                                   |
|                                   | WP2NLT                            |
|                                   |                                   |
|                                   | WP2T35                            |
|                                   |                                   |
|                                   | B003516                           |
+-----------------------------------+-----------------------------------+
| SAL Diskus 50 mcg/FP Diskus 250   | U97/060C                          |
| mcg                               |                                   |
|                                   | WP2PY5                            |
|                                   |                                   |
|                                   | E99B157                           |
|                                   |                                   |
|                                   | E99B158                           |
+-----------------------------------+-----------------------------------+
| Ventolin MDI, 90 mcg/puff         | 7ZP0053                           |
|                                   |                                   |
|                                   | 7ZP0727                           |
|                                   |                                   |
|                                   | 8ZP0909                           |
|                                   |                                   |
|                                   | 9ZP1288                           |
|                                   |                                   |
|                                   | 0ZP0164                           |
+-----------------------------------+-----------------------------------+
| Ventolin nebules, 0.098%, 2.5     | 980905                            |
| mg/3 mL                           |                                   |
|                                   | 990903                            |
+-----------------------------------+-----------------------------------+
| Cortrosyn 0.25 mg injection       | 2240697731                        |
|                                   |                                   |
|                                   | 2300199731                        |
|                                   |                                   |
|                                   | 2310299731                        |
+-----------------------------------+-----------------------------------+

There was no nonclinical pharmacology and toxicology data submitted with
this application. FP is currently approved at doses up to 1000 mcg BID
for the maintenance treatment of asthma as prophylactic therapy, the
latter dose (1000 mcg BID) for the oral corticosteroid-sparing
indication only.

Clinically relevant findings from Dr. Suarez's Clinical Pharmacology and
Biopharmaceutics review are discussed in the following section "Human
Pharmacokinetics and Pharmacodynamics."

# Human pharmacokinetics and pharmacodynamics

A brief review of pertinent human pharmacokinetics and pharmacodynamic
data for FP follows.

## Previously established data

The pharmacokinetics of FP has been well established in previous NDAs. A
brief summary of these data follows. Systemic exposure of inhaled FP
compared to intravenous administration from the individual Rotadisk,
Diskus, and CFC-MDI devices is approximately 14%, 18%, and 30%,
respectively. Systemic exposure from the Diskus inhaler is about half
that seen with the CFC-MDI. These data are derived primarily from
studies of normal volunteers and do not necessarily reflect the systemic
availability or relative delivery of each of the three devices in the
COPD population. Peak plasma concentrations occur within one hour,
regardless of device. Incomplete absorption and high first pass hepatic
metabolism result in oral bioavailability of less than 1%. The terminal
elimination half-life after intravenous or inhaled administration is 6
to 8 hours. Plasma protein binding is 91%. Metabolism of FP to an
inactive carboxylic acid metabolite occurs by the cytochrome P450
isoenzyme, CYP3A4. The major route of elimination is the feces. The
renal excretion of FP is negligible (\<0.02% of the dose) with less than
5% of a radiolabeled dose excreted in the urine as metabolites. FP does
not affect the metabolism of other drugs metabolized by the CYP3A4
enzyme system. Drugs that act as a substrate for (terfenadine) or as a
moderate inhibitor (erythromycin) of the CYP3A4 system do not
significantly alter the systemic exposure of FP. Ketoconazole increased
the systemic exposure of FP and a similar potential exists for other
strong inhibitors of the CYP3A4 enzyme system such as ritonavir.
Systemic exposure and cortisol suppression following inhalation in
asthma subjects is approximately half the exposure observed in healthy
subjects. This is likely due to airflow obstruction. The accumulation
factor following multiple dosing in asthma subjects is 1.7 and 1.5 in
healthy subjects \[hpbio\\biosum.pdf, pages 13-14\].

## Pharmacokinetic and pharmacodynamic data in this application

The sponsor supported this application with PK and PD data from three
studies. The PK and PD of FP in patients with COPD were examined in
FLTA3025 and FMS40243. The systemic exposure to FP from the FP Diskus
inhaler in the 50 mcg, 100 mcg, 250 mcg, and 500 mcg strengths in
healthy subjects was examined in FLTA1003. The results of these studies
are briefly summarized in the sections below.

### FLTA3025

FLTA3025 was a randomized, double-blind, parallel group,
placebo-controlled, comparative trial of inhaled FP 250 mcg BID and FP
500 mcg BID via the Diskus in patients with COPD. A subset of 86
patients was included in the PK/PD component of this study. Patients had
blood samples taken for measurements of plasma FP and serum cortisol
after 4 weeks of study treatment.

Key pharmacokinetic results are summarized in Table 3.1. FP AUC~last~
and FP C~max~ were higher for FP 500 than FP 250 and data suggest that 2
inhalations of FP 250 Diskus might be more than dose proportional than
one inhalation of FP 500 Diskus.

Mean FP AUC~last~ was somewhat lower in current smokers than in former
smokers. In addition, a linear relationship was observed between weight
and FP AUC~last~ for FP 500, with lower FP levels for heavier patients.
This association was not noted with FP 250
\[clinstat\\copd\\flta3025.pdf, pages 166, 4857, 4881\].

Table 3.1. Key pharmacokinetic results, FLTA 3025
\[clinstat\\copd\\flta3025.pdf, page 166; hpbio\\hpsum.pdf, page 17\].

+-----------------------+-----------------------+-----------------------+
| **PK parameter**      | **FP 250**            | **FP 500**            |
|                       |                       |                       |
|                       | **N = 31**            | **N = 27**            |
+-----------------------+-----------------------+-----------------------+
| Mean AUC~last~,       | 310.6                 | 539.0                 |
| pg.hr/mL              |                       |                       |
|                       |                       | 1.74                  |
| Ratio FP 500/FP 250   |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Mean C~max~, pg/ml    | 52.9                  | 83.6                  |
|                       |                       |                       |
| Ratio FP 500/FP 250   |                       | 1.58                  |
+-----------------------+-----------------------+-----------------------+
| T~max~, h             | 1.08                  | 1.00                  |
|                       |                       |                       |
| Ratio FP 500/FP 250   |                       | -1.01                 |
+-----------------------+-----------------------+-----------------------+

Key pharmacodynamic results are displayed in Table 3.2. FP 250 and FP
500 treatment groups had lower mean cortisol AUC~12~ and mean C~min~
than the placebo group (10% and 21%, respectively, for serum cortisol
AUC). There was a dose-response effect noted with the lowest cortisol
AUC~12~ and C~min~ in FP 500 patients \[clinstat\\copd\\flta3025.pdf,
pages 166, 4855\]. Higher mean cortisol AUC~12~ levels were noted for
current smokers than for former smokers, consistent with the lower serum
FP levels measured in current smoking. There was no relationship noted
between cortisol levels and weight \[clinstat\\copd\\flta3025.pdf, page
4857\]. These PK/PD data demonstrate measurable systemic effects of
inhaled FP.

Table 3.2. Serum cortisol results, FLTA3025
\[clinstat\\copd\\flta3025.pdf, pages 166, 4855\].

+-----------------+-----------------+-----------------+-----------------+
| **Cortisol      | **Placebo**     | **FP 250**      | **FP 500**      |
| parameter**     |                 |                 |                 |
|                 | **N = 28**      | **N = 31**      | **N = 27**      |
+-----------------+-----------------+-----------------+-----------------+
| Mean Cortisol   | 2673.4          | 2404.2          | 2102.3          |
| AUC~12~,        |                 |                 |                 |
| pmol.hr/mL      | \-              | \- 10.1%        | \- 21.4%        |
|                 |                 |                 |                 |
| ∆ vs. placebo   |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Mean C~min~,    | 123.1           | 116.7           | 85.3            |
| pmol/mL         |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

### FMS40243

This study was a comparison of the PK and PD of inhaled FP in healthy
volunteers and patients with COPD. It was a randomized, double-blind,
double dummy, 2-way crossover study that was performed in 23 subjects.
Subjects were randomized to inhaled FP 500 mcg BID from a HFA-MDI with a
Volumatic spacer device for 7 days, followed by a single inhaled dose of
1000 mcg FP and a placebo infusion, or inhaled beclomethasone
dipropionate 1000 mcg BID from a CFC-MDI with a spacer for 7 days,
followed by a single dose of inhaled placebo and FP 1000 mcg intravenous
infusion. Serial plasma FP and pre-and post-dose plasma cortisol
concentrations were measured, and urinary cortisol excretion was
calculated. Systemic exposure from inhaled FP in COPD patients was
approximately 35% (AUC~inf~) and 44% (C~max~) less than that observed in
healthy patients, but there was a large degree of variation among
subjects. Mean post-dose serum cortisol levels were 83% lower in healthy
subjects than in COPD patients \[hpbio\\biosum.pdf, pages 22-24\].
Although these data give some suggestion of decreased systemic exposure
to FP in COPD patients, they were performed with the CFC-MDI formulation
and were delivered with a spacer device, and provide little relevant
information applicable to the Diskus formulation in this application.

### FLTA1003

This study was a single center, open label, randomized, 4-way crossover
study performed in 22 healthy male and female subjects. Subjects were
randomized to receive a single 1000 mcg FP dose from the four Diskus
strengths (20 inhalations of FP Diskus 50 mcg, 10 inhalations of FP
Diskus 100 mcg, 4 inhalations of FP Diskus 250 mcg, 2 inhalations of FP
Diskus 500 mcg). Serial plasma FP concentrations were measured pre-dose
and for 24 hours post-dose. Twenty-four hour urinary cortisol excretion
was measured before and after dosing. The sponsor reported a
proportional increase in systemic exposure was seen with increasing
strength when the data were expressed as systemic exposure per
inhalation. However, pairwise comparisons of mean ratio of AUC~last~ for
1000 mcg of FP via the FP 250 Diskus and the FP 500 Diskus was 0.87,
indicating the FP 250 device was less than dose proportional to the FP
500 device in this single dose study in a population of healthy
subjects. This is in contrast to the data in FLTA3025, which suggests
that the FP 250 device was more than dose proportional to the FP 500
device. FLTA3025 was multidose, 4-week study in patients with COPD, in
contrast to FLTA1003, which was a single dose, 4-way crossover study in
healthy subjects. These differences may be the reason for the
discordance between these data. Of the two studies, FLTA3025 would be a
closer approximation to the use, indication, and population proposed in
this application.

Significant decreases in post-treatment urinary cortisol levels were
noted across all treatment groups (. These data are displayed in Table
3.3. These data show strong evidence of systemic HPA-axis effects in
normal subjects when given 1000 mcg FP by Diskus. Decreases in cortisol
excretion were noted in many subjects as soon as after the first dose of
study treatment.

Table 3.3. Urinary cortisol excretion data, FLTA1003
\[hpbio\\bio\\flta1003.pdf, page 67\].

+---------------+-----------------+-----------------+-----------------+
| **Treatment   | **Mean urinary  | **Mean urinary  | **Difference,** |
| group**       | cortisol        | cortisol        |                 |
|               | excretion,      | excretion,      | **Post-dose     |
|               | pre-dose, mcg** | post-dose,      | minus           |
|               |                 | mcg**           | pre-dose**      |
+---------------+-----------------+-----------------+-----------------+
| 50 mcg X 20   | 18.5            | 9.6             | 8.9             |
| inhalations   |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
| 100 mcg X 10  | 22.3            | 13.8            | 8.5             |
| inhalations   |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
| 250 mcg X 4   | 19.1            | 12.4            | 6.7             |
| inhalations   |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
| 500 mcg X 2   | 18.0            | 7.3             | 10.7            |
| inhalations   |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+

## Comments from Clinical Pharmacology and Biopharmaceutics review

The following comments are provided by Dr. Sandra Suarez's Clinical
Pharmacology and Biopharmaceutics review.

1.  No dose-proportional increase in AUC~t~ and C~max~ per inhalation
    was observed with increasing strengths of FP delivered from the
    Flovent Diskus. Study FLTA1003 showed that the same dose of FP (1000
    mcg) delivered from the 250 mcg and 500 mcg strengths, produce
    significantly higher cortisol suppression when delivered from the
    500 mcg strength compared to the one obtained when delivered from
    the 250 mcg strength. In addition, study FLTA3025 showed that ninety
    percent (90%) CI for the dose normalized log-transformed C~max~ and
    AUC~t~ values of FP following multiple administration of the
    treatments were out of the BE guidelines. In this case, the 250 mcg
    strength produced significantly higher C~max~ and AUC values than
    the 500 mcg strength. Therefore, strengths might not be interchanged
    with another, especially the 250 mcg and 1000 mcg strengths.

2.  Higher FP systemic exposure and lower cortisol AUC~12~ was observed
    in former smokers. According to the sponsor, no significant
    differences in FP systemic exposure or cortisol changes were
    observed between current and former smokers. However, 95% CI range
    from 0.63 to 1.35. Also, higher FP systemic exposure was seen in
    poorly reversible subjects; although no significant differences in
    FP systemic exposure or cortisol changes were observed between
    poorly reversible subjects and those considered not poorly
    reversible, 95% CI ranged from 0.73 to 1.54. The medical reviewer
    should evaluate the clinical relevance of these findings.

3.  No relationship was observed between FP systemic exposure and
    gender, race, elderly subjects (≥65 years), age, and pulmonary
    function. A relationship between FP systemic exposure and weight was
    observed after FP 500 that was not observed after FP 250 or between
    cortisol AUC~12~ and weight. However, if the sponsor chooses to
    claim in the label a lack of gender and age effect on the
    pharmacokinetics of FP delivered from the Diskus, it is necessary to
    carry out a more complex analysis of the data (including 90% CI of
    the relevant PK parameters). The sponsor is encouraged to pool all
    the FP pharmacokinetic data generated in this submission and other
    submissions before making a statement of lack of gender and age
    effect on the PK of FP. This analysis should be conducted taking
    into account the weight of the subjects.

4.  The sponsor used the FP HFA MDI with spacer to compare the PK and PD
    of inhaled FP in healthy subjects and subjects with COPD in study
    FMS40243. No study has been conducted to link the Flovent Diskus and
    the FP-HFA MDI with spacer. Therefore the relevance of the findings
    from this study to this NDA is questionable. If the sponsor wants to
    market the FP-HFA MDI device with spacer for the treatment of COPD,
    it might be necessary to conduct a complete clinical/safety and PK
    program.

*[Medical reviewer comment:]{.underline}*

*The trend to higher FP systemic exposure and lower cortisol AUC12 in
former smokers and the trend to higher FP systemic exposure in the
poorly-reversible population may indicate that these populations are at
higher risk for systemic effects. These associations do not appear to be
strong, and are not likely to have a large degree clinical relevance.
Furthermore, the findings in the poorly reversible population are not
relevant to approval of the product in the US. The sponsor performed a
subgroup analysis of this population to support European applications.
The definition of this population was based on the ERS definition of
reversibility. Patients were considered to be "poorly-reversible" of
they had an increase in percent predicted FEV~1~ of less than 10% after
albuterol at the screening visit.*

# Description of clinical data and sources

This submission refers to three pivotal clinical studies, Studies
FLTA3025, SFCA3006, and SFCA3007. These studies are submitted in support
of the efficacy of FP in the treatment of COPD. The pivotal studies were
randomized, double-blind, parallel group, placebo-controlled,
multicenter studies. Each of the pivotal studies had a 24-week treatment
duration. Study FLTA3025 evaluated the efficacy of FP 250 and FP 500
compared with placebo. SAL 50/FP 500 and FP 500 were compared with each
other and with placebo in SFCA3006. SAL 50/FP 250 and FP 250 were
compared with each other and with placebo in SFCA3007. All three studies
were similar in design, subject entrance criteria, and overall conduct
to provide replication of treatment arms across studies \[summary.pdf,
page 1\]. Replication of treatment arms is displayed in Table 4.1. The
pivotal studies for this submission are summarized in Table 4.2.

Table 4.1. Treatment arms, pivotal clinical studies, NDA 20-833
\[summary.pdf, page 2\]

+-------+--------+-------+--------+-------+--------+-------+--------+
| **St  | **Plac | **SAL | **FP   | **FP  | **SA   | **SAL | **To   |
| udy** | ebo,** | 50,** | 250,** | 5     | L50/** | 50/** | tal,** |
|       |        |       |        | 00,** |        |       |        |
|       | **N**  | **N** | **N**  |       | **FP   | **FP  | **N**  |
|       |        |       |        | **N** | 250,   | 500,  |        |
|       |        |       |        |       | N**    | N**   |        |
+-------+--------+-------+--------+-------+--------+-------+--------+
| FLT   | 206    | 0     | 216    | 218   | 0      | 0     | 640    |
| A3025 |        |       |        |       |        |       |        |
+-------+--------+-------+--------+-------+--------+-------+--------+
| SFC   | 181    | 160   | 0      | 168   | 0      | 165   | 674    |
| A3006 |        |       |        |       |        |       |        |
+-------+--------+-------+--------+-------+--------+-------+--------+
| SFC   | 185    | 177   | 183    | 0     | 178    | 0     | 723    |
| A3007 |        |       |        |       |        |       |        |
+-------+--------+-------+--------+-------+--------+-------+--------+
| T     | 570    | 337   | 399    | 386   | 178    | 165   | 3037   |
| otal, |        |       |        |       |        |       |        |
| N     |        |       |        |       |        |       |        |
+-------+--------+-------+--------+-------+--------+-------+--------+

The sponsor provided the following data in support of the safety of FP
in the treatment of COPD:

-   Safety data from the pivotal studies

```{=html}
<!-- -->
```
-   FLTA3025

-   SFCA3006

-   SFCA3007

```{=html}
<!-- -->
```
-   Supportive safety data from other studies

```{=html}
<!-- -->
```
-   AEs and HPA-axis data from clinical pharmacology study FLTA1003

-   Blinded listings of deaths and SAEs from ongoing clinical studies
    SFCB3024, SCO30003

-   Studies of Flovent MDI 500 mcg BID, FLIP63, FLIT78, FLIT97, FLIT98

-   Bone mineral density data from two long-term studies in asthma,
    FLTA3001 and FLTA3017

-   Blinded listings of deaths and SAEs from nine ongoing non-US studies
    used to support regional markets (SCO30001, SCO40002, SMS40026,
    SMS40130, SMS40308, SAM30001, FCO40003, FCO30002, and FCO40004)

A safety update, including postmarketing reports and a literature
review, is reviewed in Dr. Gilbert-McClain's Medical Officer Review of
the application for the COPD indication for the Advair product, NDA
21-077, S003.

**Table 4.2. Summary of pivotal studies, NDA 20-833, S0004
\[summary.pdf, page 20\].**

+----+-----+-----------+-------+-----------+-----+--------+--------+
| *  | *   | **        | **Dur | *         | **  | *      | **Mat  |
| *S | *St | Treatment | ation | *Design** | Num | *Diagn | erials |
| tu | udy | Groups**  | of    |           | ber | osis** | sub    |
| dy | Typ |           | t     |           | of  |        | mitted |
| Nu | e** |           | reatm |           | s   |        | in     |
| mb |     |           | ent** |           | ubj |        | this   |
| er |     |           |       |           | ect |        | a      |
| ** |     |           |       |           | s** |        | pplica |
|    |     |           |       |           |     |        | tion** |
+----+-----+-----------+-------+-----------+-----+--------+--------+
| FL | P   | FP 250    | 24    | Mul       | 640 | P      | Pr     |
| TA | ivo | mcg BID   | weeks | ticenter, |     | hysici | otocol |
| 30 | tal |           |       | ra        |     | an-dia |        |
| 25 | Ef  | FP 500    |       | ndomized, |     | gnosed | Study  |
|    | fic | mcg BID   |       | doub      |     | COPD,  | report |
|    | acy |           |       | le-blind, |     | s      |        |
|    | and | Placebo   |       | p         |     | moking | Line   |
|    | Saf | BID       |       | lacebo-co |     | hi     | li     |
|    | ety |           |       | ntrolled, |     | story, | stings |
|    |     |           |       | parallel  |     | men    |        |
|    |     |           |       | group     |     | and    | Appro  |
|    |     |           |       |           |     | women  | priate |
|    |     |           |       |           |     |        | CRFs   |
+----+-----+-----------+-------+-----------+-----+--------+--------+
| SF | P   | SAL 50    | 24    | Mul       | 691 | P      | Pr     |
| CA | ivo | mcg BID   | weeks | ticenter, |     | hysici | otocol |
| 30 | tal |           |       | ra        |     | an-dia |        |
| 06 | Ef  | FP 500    |       | ndomized, |     | gnosed | Study  |
|    | fic | mcg BID   |       | doub      |     | COPD,  | report |
|    | acy |           |       | le-blind, |     | s      |        |
|    | and | SAL 50/FP |       | p         |     | moking | Line   |
|    | Saf | 500 mcg   |       | lacebo-co |     | hi     | li     |
|    | ety | BID       |       | ntrolled, |     | story, | stings |
|    |     |           |       | parallel  |     | men    |        |
|    |     | Placebo   |       | group     |     | and    | Appro  |
|    |     | BID       |       |           |     | women  | priate |
|    |     |           |       |           |     |        | CRFs   |
+----+-----+-----------+-------+-----------+-----+--------+--------+
| SC | P   | SAL 50    | 24    | Mul       | 723 | P      | Pr     |
| FA | ivo | mcg BID   | weeks | ticenter, |     | hysici | otocol |
| 30 | tal |           |       | ra        |     | an-dia |        |
| 07 | Ef  | FP 250    |       | ndomized, |     | gnosed | Study  |
|    | fic | mcg BID   |       | doub      |     | COPD,  | report |
|    | acy |           |       | le-blind, |     | s      |        |
|    | and | SAL 50/FP |       | p         |     | moking | Line   |
|    | Saf | 250 mcg   |       | lacebo-co |     | hi     | li     |
|    | ety | BID       |       | ntrolled, |     | story, | stings |
|    |     |           |       | parallel  |     | men    |        |
|    |     | Placebo   |       | group     |     | and    | Appro  |
|    |     | BID       |       |           |     | women  | priate |
|    |     |           |       |           |     |        | CRFs   |
+----+-----+-----------+-------+-----------+-----+--------+--------+

# Clinical review methods

A summary of review methods follows, and includes a description of the
conduct of the review and an assessment of data quality.

## Conduct of the review

This submission refers to three pivotal clinical studies, Studies
FLTA3025, SFCA3006, and SFCA3007. These studies are submitted in support
of the efficacy of FP in the treatment of COPD. All three studies were
similar in design, subject entrance criteria, and overall conduct to
provide replication of treatment arms across studies. The pivotal
studies were reviewed in depth individually. The sponsor presented
individual study results and integrated the results for the studies in
the Integrated Summary of Efficacy. The integrated analysis was not
examined for this reviewer's Integrated Review of Efficacy, as
integrating the results obscured the differences in effect for the FP
250 and FP 500 groups between the studies.

Safety data was reviewed for the individual pivotal studies in depth.
Safety data from the pivotal studies and supportive safety data from
other studies were reviewed to provide this reviewer's Integrated Review
of Safety. These supportive safety data included the following:

-   AEs and HPA-axis data from clinical pharmacology study FLTA1003

-   Blinded listings of deaths and SAEs from ongoing clinical studies
    SFCB3024, SCO30003

-   Studies of Flovent MDI 500 mcg BID, FLIP63, FLIT78, FLIT97, FLIT98

-   Bone mineral density data from two long-term studies in asthma,
    FLTA3001 and FLTA3017

-   Blinded listings of deaths and SAEs from nine ongoing non-US studies
    used to support regional markets (SCO30001, SCO40002, SMS40026,
    SMS40130, SMS40308, SAM30001, FCO40003, FCO30002, and FCO40004)

The sponsor provided a safety update, including postmarketing reports
and a literature review, to support the safety of this application.
These data are reviewed in Dr. Gilbert-McClain's Medical Officer Review
of the application for the COPD indication for the Advair product, NDA
21-077, S003.

## Data quality

The following sites were identified for inspection by the Division of
Scientific Investigation (DSI):

1.  UCLA (15557)

> 10833 Le Conte Avenue Pulmonary Division, Suite 32/170
>
> Los Angeles, CA 90024
>
> Principal Investigator:
>
> Donald P. Tashkin (3854)
>
> Subinvestigators:
>
> \[ \]
>
> \[ \]
>
> \[ \]
>
> \[other\\financialinformation.pdf, page 68\]

This center enrolled the greatest number of patients in Study FLTA3025
\[clinstat\\copd\\flta3025.pdf, page 289\].

2.  Scripps Clinical/Research Foundation (13564)

> 10666N. Torrey Pines Road, Room W-207
>
> La Jolla, CA 92037
>
> Principal Investigator:
>
> Darlene Joan Elias (9058)
>
> Subinvestigators:
>
> \[ \]
>
> \[ \]
>
> \[ \]
>
> \[ \]
>
> \[other\\financialinformation.pdf, page 47\]

This center enrolled the greatest number of patients in Study SFCA3007
\[clinstat\\copd\\sfca3007.pdf, page 336\].

A request for DSI consultation was submitted. The consultation request
included selected values from the submission for comparison with the
original data source. Representative data from the NDA were provided for
the DSI team for comparison with the original data source. Data were
verified at both sites. Data from both sites appear to be acceptable for
use in the support of this application.

The sponsor excluded data from patients enrolled at the site of
Investigator #\[ \] from population and efficacy analyses of SFCA3006as
a result of a quality assurance assessment. The sponsor indicates that
there was reason to doubt the integrity of the data from patients
enrolled at this site. Data for these patients were included in the
analyses of safety \[clinstat\\copd\\sfca3006.pdf, page 92\].
Investigator #\[ \] was Dr. \[ \], of

\[ \], who was at study Site #\[ \]
\[clinstat\\other\\listofinvestigators.pdf, page 8\]. Dr. \[ \]enrolled
\[ \] patients in the study \[clinstat\\copd\\sfca3006.pdf, page 2235\].

The sponsor received a letter from Investigator #\[ \] stating that the
data generated from SFCA3006 might be unreliable. The sponsor performed
an impact analysis to determine if the removal of the data submitted by
this investigator would change interpretation of the data. The impact
analysis showed that there would be no change in the interpretation of
the data, and included data from this investigator in the study report
\[clinstat\\copd\\sfca3006.pdf, page 92\]. Investigator #\[ \] was Dr.
\[ \], who was at Site #\[ \]
\[clinstat\\other\\listofinvestigators.pdf, page 9\]. Dr. \[ \] enrolled
\[ \] patients in the study \[clinstat\\copd\\sfca3006.pdf, page
2263-2264\].

This reviewer compared results for the primary efficacy endpoint from
the impact analysis with the data including Investigator #\[ \] in the
analysis. There was essentially no difference in the change from
baseline in FEV~1~ at endpoint and at other times for treatment groups
during the treatment period. There was no impact on the inferential
statistical analysis for the primary efficacy parameter. Overall, the
data in this application appear to be acceptable for review in this
reviewer's opinion.

### Ethical standards and financial disclosure

The following items were included in this submission:

-   Debarment certification \[other\\debar.pdf\]

-   Financial disclosure statement \[other\\financialinformation.pdf\]

The sponsor certified that they did not and would not use in any
capacity the services of any person debarred under Section 306 of the
Act in connection with the application. The sponsor states that they did
not compensate clinical investigators in such a way that the total
amount could vary with the outcome of the study, and therefore there
were no disclosures in this category \[other\\financialinformation.pdf,
page 2\].

Based on available financial data the \$25,000 threshold for payments of
other sorts was exceeded in the case of one investigator, \[ \]
(Investigator #\[ \]). The sponsor conducted no analysis on the results
on study SFCA3006, since the results for the \[ \] patients enrolled at
the site represented less than 1% of patients randomized to treatment
and do not have the potential to bias the results of the study
\[other\\financialinformation.pdf, page 3\].

The sponsor stated that no clinical investigator participating in the
covered studies had a proprietary interest in the products studied
\[other\\financialinformation.pdf, page 3\].

Based on available financial data the \$50,000 threshold for equity
interest was exceeded in the case of two subinvestigators, \[ \]
(Investigator #\[ \]) and \[ \] (Investigator #\[ \]). The sponsor
conducted no analysis on the results on study FLTA3025 since the results
for the \[ \] patients enrolled at Dr. \[ \]'s site represented less
than 4% of patients randomized to treatment and do not have the
potential to bias the results of the study. The sponsor conducted no
analysis on the results on study FLTA3025 since the results for the \[
\] patients enrolled at Dr. \[ \]'s site represented less than 1% of
patients randomized to treatment and do not have the potential to bias
the results of the study \[other\\financialinformation.pdf, page 3\].

The sponsor provided a statement of Good Clinical Practices for each of
the pivotal clinical studies \[clinstat\\copd\\flta3025.pdf, page 1,
clinstat\\copd\\sfca3006.pdf, page 1, clinstat\\copd\\sfca3007.pdf, page
1\].

Overall, the data in this application appear to be acceptable for review
in this reviewer's opinion.

# Integrated review of efficacy

Review of efficacy data supporting this application follows.

## Summary and conclusions

This application included three pivotal clinical studiesFLTA3025,
SFCA3006, and SFCA3007. These studies were randomized, double-blind,
placebo-controlled, parallel group, multicenter trials that had a
similar design and were conducted in a similar manner. The studies were
designed to evaluate the safety and efficacy of SAL, FP, and the SAL/FP
combination administered BID via the Diskus over 24 weeks for the
treatment of COPD.

The majority of patients in these studies were male. The mean patient
age ranged from 61.9 to 65.2 years. A large majority of patients in
these studies were of Caucasian race, 91% to 95%. Non-Caucasian patients
were not well represented in these studies. Patients had fairly severe
dyspnea, with approximately one-third of patients experiencing dyspnea
with walking 100 yards or less on level ground. Inhaled corticosteroids
were used by 18% to 31% of patients in these studies, a fairly large
minority. The percentage of patients who were former smokers ranged from
46% to 57%. Median history of smoking ranged from 50.0 to 60.0
pack-years. The majority of patients in each of these studies were
considered to have reversibility. A patient was considered
"non-reversible" if, after 4 puffs of Ventolin MDI, there was a change
in FEV~1~ of \<12% from baseline or there was \<200 mL absolute increase
in the FEV~1~. Compliance was adequate. More than 70% of patients in
each treatment group were reported as taking 90% or more of the
prescribed doses of medication. The mean number of doses taken was
approximately 93% in each treatment group.

The primary efficacy variable for the evaluation of FP in these studies
was the pre-dose FEV~1~. The primary analysis for FP was the comparison
of the mean morning pre-dose FEV~1~ between treatment groups at
endpoint. Comparisons of FP 500 with placebo showed statistically
significant differences in mean change from baseline in pre-dose FEV~1~
in both FLTA3025 and SFCA3006, although the effect size observed in
FLTA3025 was only 50 mL, half of the "clinically significant" 100 mL the
sponsor had powered the study to detect. The effect size reported for
SFCA3006 was 113 mL. Comparisons of FP 250 with placebo showed
statistically significant differences in mean change from baseline in
pre-dose FEV~1~ only for SFCA3006, with an effect size of 108 mL, but
not for FLTA3025, which had an effect size of only 27 mL.

No active treatment group had a clinically significant difference from
the placebo group in mean change from baseline in the Global Assessment
Score (GAS) of the Chronic Bronchitis Symptom Questionnaire (CBSQ). FP
500 and FP 250 did not have a clinically significant difference from the
placebo group in the mean Transition Dyspnea Index (TDI) score. In
FLTA3025 there were slightly fewer COPD exacerbations in FP 500 and FP
250 groups than in placebo, with a dose-response effect noted.
Otherwise, the incidence of COPD exacerbations in the three pivotal
studies was fairly similar among treatment groups. The incidence of
moderate or severe COPD exacerbations in the three pivotal studies was
similar among treatment groups. There were no significant differences
between the FP and placebo groups for time to withdrawal from the study,
time to withdrawal due to COPD exacerbation, and time to withdrawal due
to COPD-related condition. Small changes from baseline in AM PEFR, daily
Ventolin use, and number of awakenings per night requiring Ventolin use
were noted for FP 250 and FP 500 groups.

The Chronic Respiratory Disease Questionnaire (CRDQ) was used to compare
changes in the COPD-related quality of life for treatment groups. No
active treatment group had a clinically significant difference from the
placebo group in mean change from baseline in the Overall score of the
CRDQ.

Subgroup analysis by smoking status showed that former smokers had
larger mean changes from baseline in FEV~1~ at endpoint for all active
study treatments than did current smokers. Subgroup analysis for the
non-reversible and reversible groups showed that the non-reversible
group had smaller mean changes from baseline in FEV~1~ at endpoint for
all active study treatments than did the reversible group. The small
number of Non-Caucasian patients makes it difficult to draw firm
conclusions on subgroup analysis by race. Subgroup analyses for gender
and age suggest that COPD exacerbations are more common in FP-treated
women and in patients greater than 65 years of age.

These studies do not support the efficacy of FP 500 or FP 250 in the
treatment of COPD. The main issues include the patient population
studied, inconsistent findings in the three pivotal studies with the
primary endpoint, the absence of strong support from the secondary
endpoints, and the failure of the studies to fully support the clinical
relevance of the primary endpoint, particularly with regard to the QOL
instrument and COPD exacerbation.

With regard to the patient population, the sponsor has not adequately
studied the efficacy of FP in non-Caucasian patients with COPD. There
are serious questions about whether the patient population studied, of
which 51% to 59% were highly reversible, is representative of the US
COPD population as a whole, for which a broad indication is sought.
Demonstration of the efficacy of FP in a more racially diverse and more
representative COPD study population would provide more convincing
evidence.

With regard to inconsistent findings on the primary endpoint, these
studies fail to support the efficacy of FP 250 because a statistically
significant difference from placebo was not noted in replicate studies.
Although statistical significance was shown for FP 500, the effect size
was relatively modest, particularly for FLTA3025, where 24 weeks of
treatment resulted in a net improvement in FEV~1~ of only 50 mL. It
should be noted that this result was also heavily driven by the
"reversible" subgroup and by subjects who had stopped smoking.

In general, most of the secondary efficacy variables did not support the
efficacy of FP 500 or FP 250. Secondary efficacy variables that would be
expected to be correlated to the primary endpoint, such as PEFR, showed
modest treatment effects and therefore do not add substantially to the
argument in favor of efficacy for this product.

The quality of life instrument (QOL), the CRDQ, does not support the
efficacy of the FP 500 or FP 250. This is particularly concerning
because all three of the pivotal studies had evaluation of QOL as one of
their primary objectives. This was included because relatively
short-term (6 months) changes in FEV~1~ have uncertain clinical
significance and do not have the same correlation with mortality that
long-term (3 year) changes would have. The small effect size in FEV~1~
combined with the observation that the patients experienced no
detectable benefit vs. placebo in a well-validated QOL instrument argues
strongly against a conclusion of efficacy for FP for the COPD
indication.

## Content

The following data were reviewed in preparation of this overview of
efficacy:

-   Efficacy data from the following pivotal studies

```{=html}
<!-- -->
```
-   FLTA3025

-   SFCA3006

-   SFCA3007

A review of efficacy data from these three pivotal clinical studies
follows below.

## Description of pivotal studies

This application included three pivotal clinical studies, FLTA3025,
SFCA3006, and SFCA3007. These studies were randomized, double-blind,
placebo-controlled, parallel group, multicenter trials that had a
similar design and were conducted in a similar manner. The studies were
designed to evaluate the safety and efficacy of SAL, FP, and the SAL/FP
combination administered BID via the Diskus over 24 weeks for the
treatment of COPD. These studies are summarized in Table 7.1.2.1
\[clinstat\\ise\\ise.pdf, pages 45-46\].

Table 6.1. Summary of pivotal studies in this application, NDA 20-833,
S004.

+-------+-----+---------------------+------+---------+------+-------+
| **    | *   | **Treatment         | **   | **D     | **Nu | **    |
| Study | *St | groups**            | Dura | esign** | mber | Diagn |
| num   | udy |                     | tion |         | of   | osis, |
| ber** | typ |                     | of   |         | pa   | age   |
|       | e** |                     | tre  |         | tien | of    |
|       |     |                     | atme |         | ts** | subje |
|       |     |                     | nt** |         |      | cts** |
+-------+-----+---------------------+------+---------+------+-------+
| FLT   | Ef  | FP 250 mcg Diskus   | 24   | Rand    | 640  | COPD, |
| A3025 | fic | BID                 | w    | omized, |      |       |
|       | acy |                     | eeks | double  |      | ≥40   |
|       | and | FP 500 mcg Diskus   |      | -blind, |      | years |
|       | saf | BID                 |      | placebo |      |       |
|       | ety |                     |      | cont    |      |       |
|       |     | Placebo Diskus BID  |      | rolled, |      |       |
|       |     |                     |      | p       |      |       |
|       |     |                     |      | arallel |      |       |
|       |     |                     |      | group   |      |       |
+-------+-----+---------------------+------+---------+------+-------+
| SFC   | Ef  | SAL 50 mcg Diskus   | 24   | Rand    | 674  | COPD, |
| A3006 | fic | BID                 | w    | omized, |      |       |
|       | acy |                     | eeks | double  |      | ≥40   |
|       | and | FP 500 mcg Diskus   |      | -blind, |      | years |
|       | saf | BID                 |      | placebo |      |       |
|       | ety |                     |      | cont    |      |       |
|       |     | SAL 50 mcg/FP 500   |      | rolled, |      |       |
|       |     | mcg Diskus BID      |      | p       |      |       |
|       |     |                     |      | arallel |      |       |
|       |     | Placebo Diskus BID  |      | group   |      |       |
+-------+-----+---------------------+------+---------+------+-------+
| SFC   | Ef  | SAL 50 mcg Diskus   | 24   | Rand    | 723  | COPD, |
| A3007 | fic | BID                 | w    | omized, |      |       |
|       | acy |                     | eeks | double  |      | ≥40   |
|       | and | FP 250 mcg Diskus   |      | -blind, |      | years |
|       | saf | BID                 |      | placebo |      |       |
|       | ety |                     |      | cont    |      |       |
|       |     | SAL 50 mcg/FP 250   |      | rolled, |      |       |
|       |     | mcg Diskus BID      |      | p       |      |       |
|       |     |                     |      | arallel |      |       |
|       |     | Placebo BID         |      | group   |      |       |
+-------+-----+---------------------+------+---------+------+-------+

### Primary efficacy endpoint

The primary efficacy variable for the evaluation of FP in these studies
was the pre-dose FEV~1~ collected at Day 1, and Weeks 1, 2, 3, 4, 6, 8,
12, 16, 20, and 24. The primary analysis for FP was the endpoint
analysis comparing the mean morning pre-dose FEV~1~ between treatment
groups. The endpoint was defined in the protocol as the final evaluable
measurement for the patient. For patients who discontinued from the
study the endpoint was the last evaluable measurement taken prior to
withdrawal. The FEV~1~ at the Discontinuation Visit was not used for any
efficacy analysis.

For SFCA3006 and SFCA3007, the 2-hour post dose FEV~1~ collected at Day
1, and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 was used to assess the
efficacy of SAL 50 and the SAL 50/FP 250 or SAL 50/FP 500 combinations
\[clinstat\\ise\\ise.pdf, pages 48-49\]. It is not relevant to the
efficacy of FP alone or in the combination and therefore will not be
discussed further in this document.

For the primary efficacy measure to evaluate FP in these studies,
treatments were compared as follows \[clinstat\\ise\\ise.pdf, pages
48-49\].

-   FP 250 or FP 500 to placebo: Pre-dose FEV~1~, to evaluate the
    efficacy of the individual component

```{=html}
<!-- -->
```
-   SAL 50/FP 250 or SAL 50/FP 500 to SAL 50: Pre-dose FEV~1~, to
    evaluate the contribution of FP 250 or FP 500 to the combination
    product

Treatment groups were compared using ANCOVA F-tests with baseline,
treatment group, and investigator as covariates
\[clinstat\\ise\\ise.pdf, page 64\].

### Secondary efficacy endpoints

Secondary efficacy variables included change from baseline in the global
and individual domains of the Chronic Bronchitis Symptoms Questionnaire
(CBSQ), the Baseline/Transition Dyspnea Index (BDI/TDI) score at each of
the treatment visits, number and percent of exacerbations of COPD, time
to first COPD exacerbation, number of withdrawals and time to
withdrawals. Morning PEFR, daily use of Ventolin, percentage of nights
with no awakenings requiring Ventolin, frequency of nighttime awakenings
requiring Ventolin, and percent of days without using Ventolin were also
summarized \[clinstat\\ise\\ise.pdf, pages 50-59\].

Summary statistics were provided for all secondary endpoints. Changes
from baseline in the Global Assessment Score (GAS) of the CBSQ were
compared between treatment groups using an ANCOVA F-test with baseline,
investigator, and treatment group as covariates. Overall and pairwise
treatment comparisons of the BDI/TDI scores were performed by ANOVA
F-test. Time to first COPD exacerbation, number of withdrawals, and time
to withdrawals were analyzed using survival analysis.
\[clinstat\\ise\\ise.pdf, page 64-67\].

The Chronic Respiratory Disease Questionnaire (CRDQ) was used to compare
changes in the COPD-related quality of life for treatment groups, as
measured by an overall score and for each of the four domains. An
improvement of at least 10 in overall score was considered to be an
overall improvement in COPD specific quality of life. At each visit,
treatment group comparisons were made comparing the change from baseline
using ANOVA, controlling for baseline and investigator. A difference
between treatment groups in mean change from baseline was considered
clinically meaningful if the difference was statistically significant
and had a minimum of ≥0.5 point improvement per question per item
\[clinstat\\ise\\ise.pdf, pages 68-70\].

### Disposition, demographics, and baseline characteristics

Patient disposition for the three pivotal studies in this application is
outlined in Table 6.2. Discontinuations were fairly frequent, ranging
from 27% to 40%. The percentage of discontinuations was fairly similar
among treatment groups, with no consistent association of
discontinuation with treatment group.

Table 6.2. Patient disposition, pivotal studies in this application, NDA
20-833, S004, \[clinstat\\ise\\ise.pdf, page 71\]

+----------+---------+---------+---------+---------+---------+---------+
|          | **Pl    | **SAL   | **FP    | **FP    | **SAL   | **SAL   |
|          | acebo** | 50**    | 250**   | 500**   | 50/**   | 50/**   |
|          |         |         |         |         |         |         |
|          |         |         |         |         | **FP    | **FP    |
|          |         |         |         |         | 250**   | 500**   |
+==========+=========+=========+=========+=========+=========+=========+
| **FL     | **N =   |         | **N =   | **N =   |         |         |
| TA3025** | 206**   |         | 216**   | 218**   |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Co       | 62      |         | 65      | 67      |         |         |
| mpleted, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Disco    | 38      |         | 35      | 33      |         |         |
| ntinued, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
|          |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| **SF     | **N =   | **N =   |         | **N =   |         | **N =   |
| CA3006** | 181**   | 160**   |         | 168**   |         | 165**   |
+----------+---------+---------+---------+---------+---------+---------+
| Co       | 62      | 72      |         | 60      |         | 68      |
| mpleted, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Disco    | 38      | 28      |         | 40      |         | 32      |
| ntinued, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
|          |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| **SF     | **N =   | **N =   | **N =   |         | **N =   |         |
| CA3007** | 185**   | 177**   | 183**   |         | 178**   |         |
+----------+---------+---------+---------+---------+---------+---------+
| Co       | 68      | 68      | 73      |         | 70      |         |
| mpleted, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Disco    | 32      | 32      | 27      |         | 30      |         |
| ntinued, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+

Patient demographics and baseline characteristics for the pivotal
studies in this application are summarized in Table 6.3. The majority of
patients in these studies were male, and the percentage of male patients
ranged from 58% to 72%. The mean patient age ranged from 61.9 to 65.2
years. A large majority of patients in these studies were of Caucasian
race, 91% to 95%. With regard to symptoms, approximately one-third of
patients experienced dyspnea with walking 100 yards or less on level
ground. Inhaled corticosteroids were used by 18% to 31% of patients in
these studies. The percentage of patients who were former smokers ranged
from 46% to 57%. Median history of smoking ranged from 50.0 to 60.0
pack-years. The majority of patients in each of these studies were
considered to have reversibility. A patient was considered
"non-reversible" if, after 4 puffs of Ventolin MDI, there was a change
in FEV~1~ of \<12% from baseline or there was \<200 mL absolute increase
in the FEV~1~. Reversible patients represented 51% to 59% of all
patients in these studies. The effects of the high percentage of
patients with reversibility in these studies are discussed further
below.

*[Reviewer comment:]{.underline}*

*The population of patients recruited for these studies raises serious
questions about the generalizability of results from this trial to the
US COPD population as a whole. Under-representation of non-Caucasian
patients in this study is a deficiency. The population studied is
characterized by long smoking histories and significant dyspnea. A
fairly large minority of the patients was taking inhaled corticosteroids
at the time of screening. One would expect these patients to more likely
to be corticosteroid-responsive than those not taking inhaled
corticosteroids, as one would expect patients with no response or a poor
response to have their treatment discontinued. It would be preferable to
perform these studies on patients who were naïve to inhaled
corticosteroids, to stratify by this variable, or recruit them to a
percent that reflects the actual off-label use of inhaled
corticosteroids in the COPD population.*

Table 6.3. Patient demographics and baseline characteristics, pivotal
studies in this application, NDA 20-833, S004, \[clinstat\\ise\\ise.pdf,
page 72\]

+----------+---------+---------+---------+---------+---------+---------+
|          | **Pl    | **SAL   | **FP    | **FP    | **SAL   | **SAL   |
|          | acebo** | 50**    | 250**   | 500**   | 50/**   | 50**    |
|          |         |         |         |         |         |         |
|          |         |         |         |         | **FP    | **/FP   |
|          |         |         |         |         | 250**   | 500**   |
+==========+=========+=========+=========+=========+=========+=========+
| **FL     | **N =   |         | **N =   | **N =   |         |         |
| TA3025** | 206**   |         | 216**   | 218**   |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Gender,  | 32/68   |         | 28/72   | 34/66   |         |         |
|          |         |         |         |         |         |         |
| \% F/ M  |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Mean     | 64.8    |         | 65.2    | 63.3    |         |         |
| age,     |         |         |         |         |         |         |
| years    |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Race, %  | 95/3/2  |         | 94/4/1  | 94/4/1  |         |         |
| C        |         |         |         |         |         |         |
| /B/Other |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Dyspnea  | 33      |         | 34      | 36      |         |         |
| score, % |         |         |         |         |         |         |
| 3 o4 4   |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| ICS use, | 31      |         | 31      | 31      |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Former   | 57      |         | 55      | 53      |         |         |
| smokers, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Pac      | 50.0    |         | 54.5    | 52.3    |         |         |
| k-years, |         |         |         |         |         |         |
|          |         |         |         |         |         |         |
| Median   |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Rev      | 59      |         | 59      | 57      |         |         |
| ersible, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
|          |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| **SF     | **N =   | **N =   |         | **N =   |         | **N =   |
| CA3006** | 181**   | 160**   |         | 168**   |         | 165**   |
+----------+---------+---------+---------+---------+---------+---------+
| Gender,  | 25/75   | 36/64   |         | 39/61   |         | 38/62   |
|          |         |         |         |         |         |         |
| \% F/ M  |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Mean     | 64.0    | 63.5    |         | 64.4    |         | 61.9    |
| age,     |         |         |         |         |         |         |
| years    |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Race, %  | 92/6/2  | 95/4/1  |         | 93/5/2  |         | 95/4/1  |
| W        |         |         |         |         |         |         |
| /B/Other |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Dyspnea  | 29      | 44      |         | 33      |         | 34      |
| score, % |         |         |         |         |         |         |
| 3 o4 4   |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| ICS use, | 18      | 31      |         | 25      |         | 28      |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Former   | 46      | 54      |         | 54      |         | 54      |
| smokers, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Pac      | 60.0    | 52.5    |         | 54.0    |         | 55.0    |
| k-years, |         |         |         |         |         |         |
|          |         |         |         |         |         |         |
| Median   |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Rev      | 56      | 51      |         | 54      |         | 53      |
| ersible, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
|          |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| **SF     | **N =   | **N =   | **N =   |         | **N =   |         |
| CA3007** | 185**   | 177**   | 183**   |         | 178**   |         |
+----------+---------+---------+---------+---------+---------+---------+
| Gender,  | 32/68   | 42/58   | 34/66   |         | 39/61   |         |
|          |         |         |         |         |         |         |
| \% F/ M  |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Mean     | 64.8    | 64.2    | 63.3    |         | 63.4    |         |
| age,     |         |         |         |         |         |         |
| years    |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Race, %  | 94/3/3  | 93/4/3  | 91/5/4  |         | 96/3/2  |         |
| W        |         |         |         |         |         |         |
| /B/Other |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Dyspnea  | 36      | 33      | 35      |         | 38      |         |
| score, % |         |         |         |         |         |         |
| 3 o4 4   |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| ICS use, | 30      | 20      | 28      |         | 23      |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Former   | 53      | 49      | 52      |         | 57      |         |
| smokers, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Pac      | 56.0    | 57.0    | 60.0    |         | 53.0    |         |
| k-years, |         |         |         |         |         |         |
|          |         |         |         |         |         |         |
| Median   |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Rev      | 55      | 55      | 55      |         | 56      |         |
| ersible, |         |         |         |         |         |         |
| %        |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+

Spirometry results at the time of screening are presented in Table 6.4.
The mean FEV~1~ for each treatment group was about 1250 mL, mean FEV~1~
% predicted was about 40%, and mean FEV~1~/FVC % was about 49%. The
degree of airway obstruction was fairly similar in each of the treatment
groups.

Table 6.4. Spirometry at screening, pivotal studies in this application,
NDA 20-833, S004, \[clinstat\\ise\\ise.pdf, page 74\]

+---------------+--------+--------+--------+--------+--------+--------+
|               | **Pla  | **SAL  | **FP   | **FP   | **SAL  | **SAL  |
|               | cebo** | 50**   | 250**  | 500**  | 50/**  | 50/**  |
|               |        |        |        |        |        |        |
|               |        |        |        |        | **FP   | **FP   |
|               |        |        |        |        | 250**  | 500**  |
+===============+========+========+========+========+========+========+
| **FLTA3025**  | **N =  |        | **N =  | **N =  |        |        |
|               | 206**  |        | 216**  | 218**  |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| n             | 206    |        | 216    | 217    |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Mean FEV~1~,  | 1254   |        | 1242   | 1266   |        |        |
| mL            |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Mean FEV~1~%  | 41.0   |        | 39.8   | 41.3   |        |        |
| predicted     |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Mean          | 47.2   |        | 46.6   | 47.8   |        |        |
| FEV~1~/FVC, % |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
|               |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| **SFCA3006**  | **N =  | **N =  |        | **N =  |        | **N =  |
|               | 181**  | 160**  |        | 168**  |        | 165**  |
+---------------+--------+--------+--------+--------+--------+--------+
| n             | 181    | 160    |        | 168    |        | 165    |
+---------------+--------+--------+--------+--------+--------+--------+
| Mean FEV~1~,  | 1317   | 1237   |        | 1233   |        | 1268   |
| mL            |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Mean FEV~1~%  | 41.5   | 40.3   |        | 41.4   |        | 40.9   |
| predicted     |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Mean          | 49.0   | 48.6   |        | 47.6   |        | 49.4   |
| FEV~1~/FVC, % |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
|               |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| **SFCA3007**  | **N =  | **N =  | **N =  |        | **N =  |        |
|               | 185**  | 177**  | 183**  |        | 178**  |        |
+---------------+--------+--------+--------+--------+--------+--------+
| n             | 185    | 177    | 183    |        | 178    |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Mean FEV~1~,  | 1289   | 1245   | 1313   |        | 1252   |        |
| mL            |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Mean FEV~1~%  | 42.1   | 41.9   | 42.0   |        | 41.4   |        |
| predicted     |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Mean          | 49.6   | 50.8   | 51.3   |        | 49.5   |        |
| FEV~1~/FVC, % |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+

Patient response to treatment with bronchodilator at screening is
summarized in Table 6.5. Reversible patients represented from 55% to 59%
of all patients in these studies. The mean % change in FEV~1~ for
reversible patients ranged from 29.8% to 32.4%. Non-reversible patients
represented 41% to 46% of all patients in this study. The mean % change
in FEV~1~ for non-reversible patients ranged from 8.6% to 9.2%. The
degree of reversibility in each of the treatment groups was similar. The
mean % change in FEV~1~ for all patients ranged from 20.0% to 22.9%.

Table 6.5. Mean change in FEV~1~ after bronchodilator treatment at
screening\*, pivotal studies in this application, NDA 20-833, S004,
\[clinstat\\ise\\ise.pdf, page 74, clinstat\\copd\\flta3025.pdf, pages
306-307, cllinstat\\copd\\sfca3006.pdf, pages 397-398,
clinstat\\copd\\sfca3007.pdf, pages 354-356\].

+------------------+------+------+------+------+------+------+------+
|                  | **P  | *    | **FP | **FP | *    | *    | *    |
|                  | lace | *SAL | 2    | 5    | *SAL | *SAL | *All |
|                  | bo** | 50** | 50** | 00** | 5    | 5    | t    |
|                  |      |      |      |      | 0/** | 0/** | reat |
|                  |      |      |      |      |      |      | ment |
|                  |      |      |      |      | **FP | **FP | grou |
|                  |      |      |      |      | 2    | 5    | ps\* |
|                  |      |      |      |      | 50** | 00** | \*** |
+==================+======+======+======+======+======+======+======+
| **FLTA3025**     |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **Reversible     | 60   |      | 59   | 57   |      |      | 59   |
| patients**       |      |      |      |      |      |      |      |
|                  | (3   |      | (3   | (3   |      |      | (3   |
| \% of population | 1.5) |      | 2.2) | 3.5) |      |      | 2.4) |
|                  |      |      |      |      |      |      |      |
| (Mean % change   |      |      |      |      |      |      |      |
| in FEV~1~)       |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **Non-reversible | 40   |      | 41   | 43   |      |      | 41   |
| patients**       |      |      |      |      |      |      |      |
|                  | (1   |      | (    | (    |      |      | (    |
| \% of population | 0.1) |      | 8.1) | 9.6) |      |      | 9.2) |
|                  |      |      |      |      |      |      |      |
| (Mean % change   |      |      |      |      |      |      |      |
| in FEV~1~)       |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **All patients** | 100  |      | 100  | 100  |      |      | 100  |
|                  |      |      |      |      |      |      |      |
| \% of population | (2   |      | (2   | (2   |      |      | (2   |
|                  | 2.8) |      | 2.4) | 3.3) |      |      | 2.9) |
| (Mean % change   |      |      |      |      |      |      |      |
| in FEV~1~)       |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **SFCA3006**     |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **Reversible     | 56   | 51   |      | 54   |      | 53   | 54   |
| patients**       |      |      |      |      |      |      |      |
|                  | (2   | (3   |      | (2   |      | (3   | (2   |
| \% of population | 8.0) | 1.6) |      | 8.6) |      | 1.6) | 9.8) |
|                  |      |      |      |      |      |      |      |
| (Mean % change   |      |      |      |      |      |      |      |
| in FEV~1~)       |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **Non-reversible | 44   | 49   |      | 46   |      | 47   | 46   |
| patients**       |      |      |      |      |      |      |      |
|                  | (    | (1   |      | (    |      | (    | (    |
| \% of population | 8.3) | 0.3) |      | 8.5) |      | 8.0) | 8.8) |
|                  |      |      |      |      |      |      |      |
| (Mean % change   |      |      |      |      |      |      |      |
| in FEV~1~)       |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **All patients** | 100  | 100  |      | 100\ |      | 100  | 100  |
|                  |      |      |      | (1   |      |      |      |
| \% of population | (1   | (2   |      | 9.2) |      | (2   | (2   |
|                  | 9.3) | 1.2) |      |      |      | 0.6) | 0.0) |
| (Mean % change   |      |      |      |      |      |      |      |
| in FEV~1~)       |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **SFCA3007**     |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **Reversible     | 55   | 55   | 55   |      | 56   |      | 55   |
| patients**       |      |      |      |      |      |      |      |
|                  | (2   | (3   | (2   |      | (2   |      | (2   |
| \% of population | 9.7) | 0.9) | 8.9) |      | 9.9) |      | 9.8) |
|                  |      |      |      |      |      |      |      |
| (Mean % change   |      |      |      |      |      |      |      |
| in FEV~1~)       |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **Non-reversible | 45   | 45   | 45   |      | 46   |      | 45   |
| patients**       |      |      |      |      |      |      |      |
|                  | (    | (    | (    |      | (    |      | (    |
| \% of population | 8.6) | 9.6) | 8.2) |      | 7.9) |      | 8.6) |
|                  |      |      |      |      |      |      |      |
| (Mean % change   |      |      |      |      |      |      |      |
| in FEV~1~)       |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+
| **All patients** | 100  | 100  | 100  |      | 100  |      | 100  |
|                  |      |      |      |      |      |      |      |
| \% of population | (2   | (2   | (1   |      | (2   |      | (2   |
|                  | 0.2) | 1.3) | 9.5) |      | 0.1) |      | 0.3) |
| (Mean % change   |      |      |      |      |      |      |      |
| in FEV~1~)       |      |      |      |      |      |      |      |
+------------------+------+------+------+------+------+------+------+

\*Calculation of response: ([Post-BD FEV]{.underline}~1~ [minus Pre-BD
FEV]{.underline}~1~[) X 100]{.underline}

Pre-BD FEV~1~

> Not reversible if result is \<12% or \<200 mL increase in FEV~1~

Reversible if result is ≥12% and ≥200 mL increase in FEV~1~

\*\*Mean change derived from data for individual treatment group data

*[Reviewer comment:]{.underline}*

*The proportion of patients enrolled in these studies with reversibility
is much higher than is found in the population of COPD patients at
large. There were 54% to 59% of patients in these studies who had
reversibility. One would expect that only up to 30% of patients to have
in increase of ≥15% in FEV~1~ after inhalation of a beta-agonist.^1,\ 2^
In addition, the degree of reversibility for the reversible population
in these studies is high---approximately 30%. The mean degree of
reversibility in the non-reversible population was also
high---approximately 9%.*

*The high proportion of patients with reversibility in this study is a
critical consideration in determining whether the results of the study
can be generalized to the COPD population as a whole. Reversible
patients were over-represented relative to their prevalence in the COPD
population as a whole, and the degree of reversibility in these patients
is much higher than would be expected for the general population of
patients with COPD^1,\ 2^. Enrichment for these highly reversible
patients would be predicted to increase the effect size. This finding
argues for restricted labeling, should the indication be granted, and
against a broad "COPD" indication.*

*Although the sponsor stratified for reversible and non-reversible
populations at randomization, initially the sponsor did not perform an
analysis of efficacy for these subgroups. The subgroup analysis was
provided by the sponsor in response to a request for information, and is
discussed later in this section.*

Compliance with study treatment is displayed in Table 6.6. The median
number of doses reported as taken was approximately 95% in each
treatment group \[clinstat\\ise\\ise.pdf, page 76\].

*[Reviewer comment:]{.underline}*

*Compliance seemed adequate to allow for assessment of efficacy,
recognizing that compliance reporting is commonly unreliable. Compliance
assessment was based on data from the Diskus dose counter, which cannot
accurately assess whether patients actually received the drug that was
dispensed.*

Table 6.6. Compliance with study treatment, pivotal studies in this
application, NDA 20-833, S004, \[clinstat\\ise\\ise.pdf, page 76\].

+----------------+--------+--------+--------+--------+--------+--------+
|                | **Pla  | **SAL  | **FP   | **FP   | **SAL  | **SAL  |
|                | cebo** | 50**   | 250**  | 50**   | 50/**  | 50/**  |
|                |        |        |        |        |        |        |
|                |        |        |        |        | **FP   | **FP   |
|                |        |        |        |        | 250**  | 500**  |
+================+========+========+========+========+========+========+
| **FLTA3025**   | 96.0   |        | 95.3   | 95.3   |        |        |
|                |        |        |        |        |        |        |
| Median rate\*, |        |        |        |        |        |        |
| %              |        |        |        |        |        |        |
+----------------+--------+--------+--------+--------+--------+--------+
| **SFCA3006**   | 95.2   | 96.4   |        | 95.9   |        | 95.8   |
|                |        |        |        |        |        |        |
| Median rate, % |        |        |        |        |        |        |
+----------------+--------+--------+--------+--------+--------+--------+
| **SFCA3007**   | 96.0   | 96.4   | 95.9   |        | 96.0   |        |
|                |        |        |        |        |        |        |
| Median rate, % |        |        |        |        |        |        |
+----------------+--------+--------+--------+--------+--------+--------+

\*Compliance rate = (Total doses from dose counter) / (2 X Number of
days on treatment) X 100

### Primary efficacy endpoint

The primary efficacy variable for the evaluation of FP in these studies
was the pre-dose FEV~1~ collected at Day 1, and Weeks 1, 2, 3, 4, 6, 8,
12, 16, 20, and 24. The primary analysis for FP was the endpoint
analysis comparing the mean morning pre-dose FEV~1~ between treatment
groups.

Because this application is concerned with the efficacy of FP and not
the SAL 50/FP combination products, the following comparisons will be
discussed:

-   FP 250 and FP 500 to placebo

```{=html}
<!-- -->
```
-   SAL 50/FP 250 and SAL 50/FP 500 to SAL 50

The following comparisons will not be discussed in this section, as they
are concerned with the evaluation of efficacy of the SAL 50 or the SAL
50/FP products:

-   SAL 50/FP 250 and SAL 50/FP 500 to placebo

```{=html}
<!-- -->
```
-   SAL 50 to placebo

```{=html}
<!-- -->
```
-   SAL 50/FP 250 to FP 250 and SAL 50/FP 500 to FP 500

Primary efficacy endpoint data for the three pivotal studies in this
application are summarized in Table 6.7. Comparisons of FP 500 with
placebo showed statistically significant differences in mean change from
baseline in pre-dose FEV~1~ in both FLTA3025 (50 mL, p = 0.010) and
SFCA3006 (113 mL, p \<0.001). Comparisons of FP 250 with placebo showed
statistically significant differences in mean change from baseline in
pre-dose FEV~1~ for SFCA3006 (108 mL, p\<0.001), but not for FLTA3025
(27 mL, p = 0.140). In FLTA 3025, there was a dose-response noted for
the small magnitude of change from baseline in pre-dose FEV~1~ for FP
500 (50 mL) and FP 250 (27 mL). The magnitude of change from baseline
for pre-dose FEV~1~ for FP 500 in SFCA3006 (113 mL) was similar to that
noted for FP 250 in SFCA3007 (108 mL) \[clinstat\\ise\\ise.pdf, pages
134, 532, 536, 540\].

Comparisons with placebo showed statistically significant differences in
mean change from baseline in pre-dose FEV~1~ at endpoint for SAL 50/FP
500 and SAL 50/FP 250. Comparisons of SAL 50/FP 500 with SAL 50 showed
statistically significant differences in mean change from baseline in
pre-dose FEV~1~ in SFCA3006 (p \<0.001), with an "added" effect size
attributable to FP of 49 mL (see table, below). Comparisons of SAL 50/FP
250 with SAL 50 showed statistically significant differences in mean
change from baseline in pre-dose FEV~1~ in SFCA3007 (p = 0.012), with an
"added" effect size attributable to FP of 74 mL (see table, below)
\[clinstat\\ise\\ise.pdf, pages 134, 532, 536, 540\].

Differences from placebo in mean change from baseline in pre-dose FEV~1~
were noted at Week 1 for the FP and SAL 50/FP products although the
magnitude of the differences for FP 500 (36 mL) and FP 250 (18 mL) were
quite small \[clinstat\\ise\\ise.pdf, pages 509, 515, 521\].

*[Reviewer comment:]{.underline}*

*A statistically significant difference from placebo in the primary
efficacy endpoint was noted in replicate studies for FP 500 only, not
for FP 250. There were large differences in the degree of effect noted
in these studies, with a small effect in FLTA3025, particularly for FP
250. The reason for the large differences in the effect is unclear.
Comparisons of the SAL 50/FP combination products with SAL 50 indicate
that FP provided some efficacy to the combination product.*

*The sponsor integrated the results for the primary efficacy endpoint.
This analysis will not be discussed, as integrating the results obscures
the differences in effect for the FP 250 and FP 500 groups, and is not
appropriate for efficacy data.*

*These studies fail to support the efficacy of FP 250, as a
statistically significant difference from placebo was not noted in
replicate studies. Although these primary efficacy endpoint data support
the efficacy of FP 500, the modest effects on FEV~1~ will need to be
examined in light of secondary endpoint and quality of life results, and
balanced against safety concerns for this high dose of FP.*

**Table 6.7. Mean change in pre-dose FEV~1~** from baseline, primary
efficacy variable, pivotal studies in this application, NDA 20-833,
S004, \[clinstat\\ise\\ise.pdf, pages 134, 532, 536, 540\].

+-------------------+-------+-------+-------+-------+-------+-------+
|                   | *     | **SAL | **FP  | **FP  | **SAL | **SAL |
|                   | *Plac | 50**  | 250** | 500** | 50/** | 50/** |
|                   | ebo** |       |       |       |       |       |
|                   |       |       |       |       | **FP  | **FP  |
|                   |       |       |       |       | 250** | 500** |
+===================+=======+=======+=======+=======+=======+=======+
| **FLTA3025**      |       |       |       |       |       |       |
+-------------------+-------+-------+-------+-------+-------+-------+
| Baseline          | 1203  |       | 1207  | 1246  |       |       |
|                   |       |       |       |       |       |       |
| Mean FEV~1~, ml   | \(    |       | \(    | \(    |       |       |
|                   | 204\) |       | 215\) | 218\) |       |       |
| \(n\)             |       |       |       |       |       |       |
+-------------------+-------+-------+-------+-------+-------+-------+
| Endpoint          | **0** |       | *     | *     |       |       |
|                   |       |       | *27** | *50** |       |       |
| **Difference from | 1221  |       |       |       |       |       |
| placebo**         |       |       | *     | *     |       |       |
|                   | \(    |       | *(0.1 | *(0.0 |       |       |
| **Mean change,    | 199\) |       | 40)** | 10)** |       |       |
| ml**              |       |       |       |       |       |       |
|                   |       |       | 1240  | 1301  |       |       |
| **p value vs.     |       |       |       |       |       |       |
| placebo**         |       |       | \(    | \(    |       |       |
|                   |       |       | 211\) | 210\) |       |       |
| Mean FEV~1~, ml   |       |       |       |       |       |       |
|                   |       |       |       |       |       |       |
| \(n\)             |       |       |       |       |       |       |
+-------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3006**      |       |       |       |       |       |       |
+-------------------+-------+-------+-------+-------+-------+-------+
| Baseline          | 1282  | 1192  |       | 1174  |       | 1254  |
|                   |       |       |       |       |       |       |
| Mean FEV~1~, ml   | \(    | \(    |       | \(    |       | \(    |
|                   | 181\) | 159\) |       | 166\) |       | 163\) |
| \(n\)             |       |       |       |       |       |       |
+-------------------+-------+-------+-------+-------+-------+-------+
| Endpoint          | **0** | **    |       | **    |       | **    |
|                   |       | 111** |       | 113** |       | 160** |
| **Difference from | 1292  |       |       |       |       |       |
| placebo**         |       | **(   |       | **(   |       | **(   |
|                   | \(    | \<0.0 |       | \<0.0 |       | \<0.0 |
| **Mean change,    | 171\) | 01)** |       | 01)** |       | 01)** |
| ml**              |       |       |       |       |       |       |
|                   |       | 1303  |       | 1298  |       | **(   |
| **p value vs.     |       |       |       |       |       | \<0.0 |
| placebo**         |       | \(    |       | \(    |       | 01)** |
|                   |       | 158\) |       | 160\) |       |       |
| **p value vs. SAL |       |       |       |       |       | 1410  |
| 50**              |       |       |       |       |       |       |
|                   |       |       |       |       |       | \(    |
| Mean FEV~1~, ml   |       |       |       |       |       | 156\) |
|                   |       |       |       |       |       |       |
| \(n\)             |       |       |       |       |       |       |
+-------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3007**      |       |       |       |       |       |       |
+-------------------+-------+-------+-------+-------+-------+-------+
| Baseline          | 1232  | 1205  | 1236  |       | 1207  |       |
|                   |       |       |       |       |       |       |
| Mean FEV~1~, ml   | \(    | \(    | \(    |       | \(    |       |
|                   | 185\) | 177\) | 183\) |       | 178\) |       |
| \(n\)             |       |       |       |       |       |       |
+-------------------+-------+-------+-------+-------+-------+-------+
| Endpoint          | **0** | *     | **    |       | **    |       |
|                   |       | *90** | 108** |       | 164** |       |
| **Difference from | 1240  |       |       |       |       |       |
| placebo**         |       | **(   | **(   |       | **(   |       |
|                   | \(    | \<0.0 | \<0.0 |       | \<0.0 |       |
| **Mean change,    | 172\) | 01)** | 01)** |       | 10)** |       |
| ml**              |       |       |       |       |       |       |
|                   |       | 1303  | 1351  |       | *     |       |
| **p value vs.     |       |       |       |       | *(0.0 |       |
| placebo**         |       | \(    | \(    |       | 12)** |       |
|                   |       | 168\) | 175\) |       |       |       |
| **p value vs. SAL |       |       |       |       | 1375  |       |
| 50**              |       |       |       |       |       |       |
|                   |       |       |       |       | \(    |       |
| Mean FEV~1~, ml   |       |       |       |       | 165\) |       |
|                   |       |       |       |       |       |       |
| \(n\)             |       |       |       |       |       |       |
+-------------------+-------+-------+-------+-------+-------+-------+

ANCOVA, baseline as covariate

p values for overall comparisons at endpoint for each study:

FLTA3025: 0.035

SFCA3006: \<0.001

SFCA3007: \<0.001

### Secondary efficacy endpoints

Secondary efficacy variables included change from baseline in the global
and individual domains of the CBSQ, the BDI/TDI score at each of the
treatment visits, number and percent of exacerbations of COPD, time to
first COPD exacerbation, number of withdrawals and time to withdrawals.
Morning PEFR, daily use of Ventolin, percentage of nights with no
awakenings requiring Ventolin, frequency of nighttime awakenings
requiring Ventolin, and percent of days without using Ventolin were also
summarized \[clinstat\\ise\\ise.pdf, pages 50-59\]. These data are
discussed below.

#### Chronic Bronchitis Symptom Questionnaire

The CBSQ evaluated cough frequency and severity, sputum release, and
chest discomfort on a 0 to 4, 5-point scale. Individual scores were
summed to provide a Global Assessment Score (GAS). The maximum possible
GAS was 16. Patients were required to have a minimum score of 4 at
baseline to qualify for randomization. The sponsor determined that the
Minimally Clinically Important Change (MCIC) in the CBSQ was 1.4 points
in an analysis of patients completing at least 8 weeks of this study
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 11\]. Results of the
Chronic Bronchitis Symptom Questionnaire are displayed in Table 6.8.

Differences from placebo in the mean change from baseline in the GAS at
endpoint were compared. No active treatment group had a clinically
significant difference from the placebo group in mean change from
baseline in the GAS.

Table 6.8. Mean change from baseline in the global assessment score
(GAS) of the CBSQ, pivotal studies in this application, NDA 20-833,
S004, \[clinstat\\ise\\ise.pdf, page 138\].

+--------------------+-------+-------+-------+-------+-------+-------+
|                    | *     | **SAL | **FP  | **FP  | **SAL | **SAL |
|                    | *Plac | 50**  | 250** | 500** | 50/** | 50/** |
|                    | ebo** |       |       |       |       |       |
|                    |       |       |       |       | **FP  | **FP  |
|                    |       |       |       |       | 250** | 500** |
+====================+=======+=======+=======+=======+=======+=======+
| **FLTA3025**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Mean change in GAS | 0.9   |       | 1.4   | 1.4   |       |       |
| at endpoint        |       |       |       |       |       |       |
|                    | 0     |       | 0.5   | 0.5   |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3006**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Mean change in GAS | 1.5   | 1.9   |       | 1.6   |       | 1.8   |
| at endpoint        |       |       |       |       |       |       |
|                    | 0     | 0.4   |       | 0.1   |       | 0.3   |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3007**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Mean change in GAS | 1.4   | 1.5   | 2.2   |       | 2.1   |       |
| at endpoint        |       |       |       |       |       |       |
|                    | 0     | 0.1   | 0.8   |       | 0.7   |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+

\*Minimal clinically significant change = 1.4 points

*[Reviewer comment:]{.underline}*

*The CBSQ does not support the efficacy of the FP 500 or FP 250, or for
the SAL50/FP combination products. This is an important observation, as
this endpoint evaluates symptoms of patients with COPD, and is not
directly related to measures of bronchodilatation, as is the primary
efficacy endpoint.*

#### Baseline/Transition Dyspnea Indices

The degree of functional impairment at baseline due to dyspnea, the
magnitude of task to provoke dyspnea, and the magnitude of effort that
provoked dyspnea were rated on a 0 to 4, 5-point scale to derive the
BDI. The maximum BDI score was 12. The TDI assessed changes from
baseline in functional impairment, magnitude of task, and magnitude of
effort and were assessed at each subsequent visit with a -3 to +3,
seven-point scale. The sponsor considered a clinically important TDI
score to be ≥1.0. Results of the BDI/TDI are presented in Table 6.9.

Differences from placebo in the mean TDIs at endpoint were compared.
Only SAL50/FP 500 had a clinically significant difference from the
placebo group. No other active treatment group had a clinically
significant difference from the placebo group in mean TDI.

Table 6.9. Mean Transition Dyspnea Index (TDI) scores, pivotal studies
in this application, NDA 20-833, S004, \[clinstat\\ise\\ise.pdf, page
140\].

+--------------------+-------+-------+-------+-------+-------+-------+
|                    | *     | **SAL | **FP  | **FP  | **SAL | **SAL |
|                    | *Plac | 50**  | 250** | 500** | 50/** | 50/** |
|                    | ebo** |       |       |       |       |       |
|                    |       |       |       |       | **FP  | **FP  |
|                    |       |       |       |       | 250** | 500** |
+====================+=======+=======+=======+=======+=======+=======+
| **FLTA3025**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Mean TDI at        | 0.5   |       | 0.9   | 1.2   |       |       |
| endpoint           |       |       |       |       |       |       |
|                    | 0     |       | 0.4   | 0.7   |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3006**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Mean TDI at        | 0.4   | 0.9   |       | 1.3   |       | 2.1   |
| endpoint           |       |       |       |       |       |       |
|                    | 0     | 0.5   |       | 0.9   |       | 1.7   |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3007**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Mean TDI at        | 1.0   | 1.6   | 1.7   |       | 1.7   |       |
| endpoint           |       |       |       |       |       |       |
|                    | 0     | 0.6   | 0.7   |       | 0.7   |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+

\*Minimal clinically significant change = 1.0 points

*[Reviewer comment:]{.underline}*

*The TDI does not support the efficacy of the FP 500 or FP 250.*

### COPD exacerbations

The incidence of COPD exacerbations in these studies is summarized in
Table 6.9. In FLTA3025 there were slightly fewer COPD exacerbations in
FP 500 and FP 250 groups than in placebo, with a dose-response effect
noted. Otherwise, the incidence of COPD exacerbations in the three
pivotal studies was fairly similar among treatment groups. The incidence
of moderate or severe COPD exacerbations in the three pivotal studies
was similar among treatment groups \[clinstat\\ise\\ise.pdf, pages
143-144\].

Table 6.9. Incidence of COPD exacerbations, pivotal studies in this
application, NDA 20-833, S004, \[clinstat\\ise\\ise.pdf, page 143,
144\].

+----------------------+-------+-------+-------+-------+-------+-------+
|                      | *     | **SAL | **FP  | **FP  | **SAL | **SAL |
|                      | *Plac | 50**  | 250** | 500** | 50/** | 50/** |
|                      | ebo** |       |       |       |       |       |
|                      |       |       |       |       | **FP  | **FP  |
|                      |       |       |       |       | 250** | 500** |
+======================+=======+=======+=======+=======+=======+=======+
| **FLTA3025**         | **N = |       | **N = | **N = |       |       |
|                      | 206** |       | 216** | 218** |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| At least one COPD    | 51    |       | 48    | 45    |       |       |
| exacerbation, %      |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| At least one         | 43    |       | 40    | 48    |       |       |
| moderate or severe   |       |       |       |       |       |       |
| COPD exacerbation, % |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3006**         | **N = | **N = |       | **N = |       | **N = |
|                      | 181** | 160** |       | 168** |       | 165** |
+----------------------+-------+-------+-------+-------+-------+-------+
| At least one COPD    | 44    | 39    |       | 46    |       | 41    |
| exacerbation, %      |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| At least one         | 35    | 38    |       | 40    |       | 37    |
| moderate or severe   |       |       |       |       |       |       |
| COPD exacerbation, % |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3007**         | **N = | **N = | **N = |       | **N = |       |
|                      | 185** | 177** | 183** |       | 178** |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| At least one COPD    | 39    | 37    | 43    |       | 40    |       |
| exacerbation, %      |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| At least one         | 34    | 31    | 38    |       | 34    |       |
| moderate or severe   |       |       |       |       |       |       |
| COPD exacerbation, % |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+

There were no significant differences between the FP and placebo groups
for time to withdrawal from the study, time to withdrawal due to COPD
exacerbation, and time to withdrawal due to COPD-related condition
\[clinstat\\ise\\ise.pdf, pages 146-147\].

*[Reviewer comment:]{.underline}*

*With the exception of FLTA3025, these studies show no effect of FP on
the incidence of all COPD exacerbations or moderate or severe COPD
exacerbations. These data do not support the efficacy of FP 250 or FP
500 in this population.*

#### AM PEFR

Mean change from baseline in AM PEFR in the three pivotal studies in
this application is summarized in Table 6.10. Small changes from
baseline in AM PEFR were noted for FP 500 and FP 250 groups. Larger
changes from baseline in AM PEFR were noted for SAL 50, SAL 50/FP 250,
and SAL 50/FP 500 groups \[clinstat\\ise\\ise.pdf, page 148\].

Table 6.10. Mean change from baseline in AM PEFR, pivotal studies in
this application, NDA 20-833, S004, \[clinstat\\ise\\ise.pdf, page
148\].

+----------------------+-------+-------+-------+-------+-------+-------+
|                      | *     | **SAL | **FP  | **FP  | **SAL | **SAL |
|                      | *Plac | 50**  | 250** | 500** | 50/** | 50/** |
|                      | ebo** |       |       |       |       |       |
|                      |       |       |       |       | **FP  | **FP  |
|                      |       |       |       |       | 250** | 500** |
+======================+=======+=======+=======+=======+=======+=======+
| **FLTA3025**         | **N = |       | **N = | **N = |       |       |
|                      | 205** |       | 213** | 218** |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| Mean change, L/min   | -1.9  |       | 8.8   | 9.4   |       |       |
|                      |       |       |       |       |       |       |
| Difference from      | 0     |       | 10.7  | 11.3  |       |       |
| placebo              |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3006**         | **N = | **N = |       | **N = |       | **N = |
|                      | 181** | 160** |       | 168** |       | 165** |
+----------------------+-------+-------+-------+-------+-------+-------+
| Mean change, L/min   | -2.7  | 16.8  |       | 12.9  |       | 31.9  |
|                      |       |       |       |       |       |       |
| Difference from      | 0     | 19.5  |       | 15.6  |       | 34.6  |
| placebo              |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3007**         | **N = | **N = | **N = |       | **N = |       |
|                      | 185** | 177** | 183** |       | 178** |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| Mean change, L/min   | 0.8   | 14.7  | 11.3  |       | 30.6  |       |
|                      |       |       |       |       |       |       |
| Difference from      | 0     | 13.9  | 10.5  |       | 29.8  |       |
| placebo              |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+

*[Reviewer note:]{.underline}*

*These data are supportive of the efficacy of FP in this population,
however PEFR results are likely to be fairly closely correlated with the
FEV~1~ results and other measures of bronchodilatation.*

#### Daily Ventolin use

Mean change from baseline in daily Ventolin use in the three pivotal
studies in this application is summarized in Table 6.11. Small changes
from baseline in mean change from baseline in daily Ventolin use were
noted for FP 500 and FP 250 groups. Larger changes from baseline were
noted for SAL 50, SAL 50/FP 250, and SAL 50/FP 500 groups
\[clinstat\\ise\\ise.pdf, page 148\].

Table 6.11. Mean change from baseline in daily Ventolin use, pivotal
studies in this application, NDA 20-833, S004, \[clinstat\\ise\\ise.pdf,
page 151\].

+----------------------+-------+-------+-------+-------+-------+-------+
|                      | *     | **SAL | **FP  | **FP  | **SAL | **SAL |
|                      | *Plac | 50**  | 250** | 500** | 50/** | 50/** |
|                      | ebo** |       |       |       |       |       |
|                      |       |       |       |       | **FP  | **FP  |
|                      |       |       |       |       | 250** | 500** |
+======================+=======+=======+=======+=======+=======+=======+
| **FLTA3025**         | **N = |       | **N = | **N = |       |       |
|                      | 204** |       | 212** | 215** |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| Mean change,         | 0.7   |       | -0.1  | -0.2  |       |       |
| puffs/day            |       |       |       |       |       |       |
|                      | 0     |       | -0.8  | -0.9  |       |       |
| Difference from      |       |       |       |       |       |       |
| placebo              |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3006**         | **N = | **N = |       | **N = |       | **N = |
|                      | 182** | 174** |       | 177** |       | 172** |
+----------------------+-------+-------+-------+-------+-------+-------+
| Mean change,         | 0.5   | -0.9  |       | -0.4  |       | -1.2  |
| puffs/day            |       |       |       |       |       |       |
|                      | 0     | -1.4  |       | -0.9  |       | -1.7  |
| Difference from      |       |       |       |       |       |       |
| placebo              |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3007**         | **N = | **N = | **N = |       | **N = |       |
|                      | 185** | 177** | 183** |       | 178** |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| Mean change,         | 0.1   | -0.7  | -0.2  |       | -1.0  |       |
| puffs/day            |       |       |       |       |       |       |
|                      | 0     | -0.8  | -0.3  |       | -1.1  |       |
| Difference from      |       |       |       |       |       |       |
| placebo              |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+

*[Reviewer note:]{.underline}*

*These data are supportive of the efficacy of FP in this population.
However, as with AM PEFR data, Ventolin use results are likely to be
fairly closely correlated with the FEV~1~ results and other measures of
bronchodilatation.*

#### Awakenings requiring Ventolin use

Mean change from baseline in daily Ventolin use in the three pivotal
studies in this application is summarized in Table 6.12. Small changes
from baseline in mean change from baseline in number of awakenings per
night requiring Ventolin use were noted for FP 500 and FP 250 groups.
Larger changes from baseline were noted for SAL 50, SAL 50/FP 250, and
SAL 50/FP 500 groups \[clinstat\\ise\\ise.pdf, page 153\].

Table 6.11. Mean change from baseline in number of awakenings per night
requiring Ventolin use, pivotal studies in this application, NDA 20-833,
S004, \[clinstat\\ise\\ise.pdf, page 153\].

+----------------------+-------+-------+-------+-------+-------+-------+
|                      | *     | **SAL | **FP  | **FP  | **SAL | **SAL |
|                      | *Plac | 50**  | 250** | 500** | 50/** | 50/** |
|                      | ebo** |       |       |       |       |       |
|                      |       |       |       |       | **FP  | **FP  |
|                      |       |       |       |       | 250** | 500** |
+======================+=======+=======+=======+=======+=======+=======+
| **FLTA3025**         | **N = |       | **N = | **N = |       |       |
|                      | 202** |       | 211** | 212** |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| Mean change,         | 0.11  |       | -0.05 | -0.05 |       |       |
| awakenings/night     |       |       |       |       |       |       |
|                      | 0     |       | -0.16 | -0.16 |       |       |
| Difference from      |       |       |       |       |       |       |
| placebo              |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3006**         | **N = | **N = |       | **N = |       | **N = |
|                      | 175** | 153** |       | 162** |       | 157** |
+----------------------+-------+-------+-------+-------+-------+-------+
| Mean change,         | 0.10  | -0.09 |       | -0.08 |       | -0.04 |
| awakenings/night     |       |       |       |       |       |       |
|                      | 0     | -0.19 |       | -0.18 |       | -0.14 |
| Difference from      |       |       |       |       |       |       |
| placebo              |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3007**         | **N = | **N = | **N = |       | **N = |       |
|                      | 181** | 174** | 177** |       | 172** |       |
+----------------------+-------+-------+-------+-------+-------+-------+
| Mean change,         | 0.02  | -0.06 | -0.03 |       | -0.12 |       |
| awakenings/night     |       |       |       |       |       |       |
|                      | 0     | -0.08 | -0.05 |       | -0.14 |       |
| Difference from      |       |       |       |       |       |       |
| placebo              |       |       |       |       |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+

*[Reviewer note:]{.underline}*

*These data are supportive of the efficacy of FP in this population.
However, as with AM PEFR data and Ventolin use, these data are likely to
be fairly closely correlated with the FEV~1~ results and other measures
of bronchodilatation.*

### Health-related quality of life instrument

QOL assessment was one of the pre-specified objectives of all three
pivotal studies. COPD-related quality of life was evaluated using the
Chronic Respiratory Disease Questionnaire (CRDQ). The CRDQ contains 20
questions in 4 domains: dyspnea, fatigue, emotional function, and
mastery. An overall score, the sum of the scores for all 20 questions,
was the primary health-related quality of life endpoint. An improvement
in the Overall score of at least 10.0 points was considered to be a
clinically significant improvement in COPD-specific quality of life.
Results of the Chronic Bronchitis Symptom Questionnaire are displayed in
Table 6.12.

Differences from placebo in the mean change from baseline at endpoint in
the Overall score of the CRDQ were compared. No active treatment group
had a clinically significant difference from the placebo group in mean
change from baseline in the Overall score of the CRDQ.

Table 6.12. Mean change from baseline for Overall score of CRDQ, pivotal
studies in this application, NDA 20-833, S004, \[clinstat\\ise\\ise.pdf,
page 171\].

+--------------------+-------+-------+-------+-------+-------+-------+
|                    | *     | **SAL | **FP  | **FP  | **SAL | **SAL |
|                    | *Plac | 50**  | 250** | 500** | 50/** | 50/** |
|                    | ebo** |       |       |       |       |       |
|                    |       |       |       |       | **FP  | **FP  |
|                    |       |       |       |       | 250** | 500** |
+====================+=======+=======+=======+=======+=======+=======+
| **FLTA3025**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Mean Overall score | 1.0   |       | 5.1   | 9.1   |       |       |
| at endpoint        |       |       |       |       |       |       |
|                    | 0     |       | 4.1   | 8.1   |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3006**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Mean Overall score | 5.0   | 8.0   |       | 4.8   |       | 10.0  |
| at endpoint        |       |       |       |       |       |       |
|                    | 0     | 3.0   |       | 1.8   |       | 5.0   |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3007**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Mean Overall score | 5.0   | 6.4   | 10.4  |       | 10.0  |       |
| at endpoint        |       |       |       |       |       |       |
|                    | 0     | 1.4   | 5.4   |       | 5.0   |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+

Minimal clinically significant change ≥ 10.0 points

*[Reviewer comment:]{.underline}*

*No active treatment group had a clinically significant difference from
the placebo group in the Overall score. As there was no clinically
significant differences from the placebo group in the Overall score, any
changes in individual domains or summary scores provide little
meaningful information. These data provide no additional support for the
efficacy of FP in this population. This is an important negative
finding, since one of the stated objectives of this study was to compare
the health-related quality of life in COPD patients receiving active
treatment compared to placebo over this 24-week study, in part to
corroborate the clinical importance of relatively small, short-term
changes in FEV~1~.*

## Subgroup analyses, smoking status and reversibility

The sponsor provided subgroup analyses of efficacy by smoking status and
for the reversible and non-reversible groups. These subgroup analyses
are discussed below.

### Smoking status, subgroup analysis

The sponsor provided a post-hoc analysis of efficacy by patient smoking
status for exploratory purposes. The sponsor provided only integrated
data for this analysis in the Integrated Summary of Efficacy (ISE), and
did not provide the results for individual studies
\[clinstat\\ise\\ise.pdf, page 205\]. This reviewer will not examine the
sponsor's integrated data for the primary efficacy endpoint because of
the large differences in effect size between these studies. This
document will review the primary efficacy endpoint data from the
individual studies for this subgroup analysis, instead. Integrated
secondary efficacy endpoint data will be reviewed, as presented in the
sponsor's ISE.

Former smokers had larger mean changes from baseline in FEV~1~ at
endpoint for all active study treatments than did current smokers. These
data are displayed in Table 6.13. Current smokers showed responses to FP
500 and FP 250 that were smaller and more modest than did former smokers
in SFCA3006 and SFCA3007. Current smokers showed no response to FP 500
or FP 250 in FLTA3025, in contrast to the other two studies.

**Table 6.13. Mean change from baseline in FEV~1~** at endpoint, by
smoking status, pivotal studies in this application, NDA 20-833, S004,
\[clinstat\\copd\\flta3025.pdf, page 101; clinstat\\copd\\sfca3006.pdf,
page 130; clinstat\\copd\\sfca.pdf, page 115\].

+--------------------+-------+-------+-------+-------+-------+-------+
|                    | *     | **SAL | **FP  | **FP  | **SAL | **SAL |
|                    | *Plac | 50**  | 250** | 500** | 50/** | 50/** |
|                    | ebo** |       |       |       |       |       |
|                    |       |       |       |       | **FP  | **FP  |
|                    |       |       |       |       | 250** | 500** |
+====================+=======+=======+=======+=======+=======+=======+
| **FLTA3025**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Current smokers    | 31    |       | -5    | 17    |       |       |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     |       | -36   | 14    |       |       |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Former smokers     | -5    |       | 72    | 100   |       |       |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     |       | 77    | 105   |       |       |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3006**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Current smokers    | -21   | 78    |       | 73    |       | 130   |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     | 99    |       | 94    |       | 151   |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Former smokers     | 16    | 132   |       | 139   |       | 179   |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     | 116   |       | 123   |       | 163   |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3007**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Current smokers    | 4     | 96    | 80    |       | 127   |       |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     | 92    | 76    |       | 123   |       |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Former smokers     | -3    | 86    | 136   |       | 193   |       |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     | 89    | 139   |       | 196   |       |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+

The sponsor also examined other efficacy endpoints by patient smoking
status. As noted above, the sponsor presented integrated data from the
three pivotal studies. These data are discussed below.

The GAS of the CBSQ showed no clinically significant differences from
placebo for any treatment group in both former and current smokers. The
GAS of the CBSQ numerically favored former smokers
\[clinstat\\ise\\ise.pdf, page 207\].

Mean TDI scores showed clinically significant differences from placebo
for former smokers for FP 500, SAL 50/FP 500, and SAL 50/FP 250. Mean
TDI scores showed clinically significant differences from placebo for
current smokers for SAL 50/FP 500. TDI scores numerically favored former
smokers \[clinstat\\ise\\ise.pdf, page 209\].

The incidence of COPD exacerbations of any intensity was similar between
smoking status subgroups. The incidence of moderate or severe COPD
exacerbations was slightly lower in FP 500 and FP 250 groups when
compared with placebo. There was no difference in survival analyses for
time to first COPD exacerbation of any intensity or time to first
moderate or severe COPD exacerbation for FP 500 or FP 500 with regards
to smoking status \[clinstat\\ise\\ise.pdf, pages 209-210\].

The Overall score of the CRDQ, the health-related quality of life
instrument, showed no clinically significant differences from placebo
for any treatment group in both former and current smokers. The Overall
score of the CBSQ numerically favored former smokers
\[clinstat\\ise\\ise.pdf, page 247\].

*[Reviewer comment:]{.underline}*

*These data suggest that patients who stopped smoking prior to the
conduct of the study had a greater treatment effect from FP 500 and FP
250. It is unclear why there is such a large discordance in the response
to FP for the primary efficacy endpoint in current smokers between
FLTA3025 and the other two studies. The most prominent treatment effects
were noted for the primary efficacy endpoint, change in FEV~1~ from
baseline at endpoint. Secondary efficacy endpoint results showed smaller
differences between current and former smokers.*

*It has been well established by the Lung Health Study^3^ that smoking
cessation has a far greater impact on lung function and long-term
survival of the COPD patient than any pharmacological intervention. It
is therefore not unreasonable to attribute some of the improvement in
FEV~1~ observed during the study to abstention from smoking.*

### "Non-reversible" population, subgroup analysis

Assignment to study drug was to be stratified according to the patients'
response to reversibility testing with Ventolin at screening to a
non-reversible group and a reversible group. Non-reversible patients
were defined as having an absolute volume increase \<200 mL or an
absolute volume increase of ≥200 mL with baseline FEV~1~ reversibility
of \<12%. Reversible patients were defined as having an absolute volume
increase ≥200 mL with baseline FEV~1~ reversibility of ≥12%. The sponsor
provided only integrated data for this analysis in the Integrated
Summary of Efficacy (ISE), and did not provide the results for
individual studies \[clinstat\\ise\\ise.pdf, page 212\]. This reviewer
will not examine the sponsor's integrated data for the primary efficacy
endpoint because of the large differences in effect size between these
studies. This document will review the primary efficacy endpoint data
from the individual studies for this subgroup analysis, instead.
Integrated secondary efficacy endpoint data will be reviewed, as
presented in the sponsor's ISE.

The non-reversible group had smaller mean changes from baseline in
FEV~1~ at endpoint for all active study treatments than did the
reversible group. These data are displayed in Table 6.13. Both the
non-reversible and reversible groups in FLTA3025 showed responses to FP
500 and FP 250 that were much smaller than the same groups in SFCA3006
and SFCA3007.

**Table 6.12. Mean change from baseline in FEV~1~** at endpoint,
non-reversible and reversible groups, pivotal studies in this
application \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf page 18;
NDA 20-833, S004, \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, page
9; NDA 20-833, S004, \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf,
page 14\].

+--------------------+-------+-------+-------+-------+-------+-------+
|                    | *     | **SAL | **FP  | **FP  | **SAL | **SAL |
|                    | *Plac | 50**  | 250** | 500** | 50/** | 50/** |
|                    | ebo** |       |       |       |       |       |
|                    |       |       |       |       | **FP  | **FP  |
|                    |       |       |       |       | 250** | 500** |
+====================+=======+=======+=======+=======+=======+=======+
| **FLTA3025**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Non-reversible     | -17   |       | -15   | 21    |       |       |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     |       | 2     | 38    |       |       |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Reversible         | 29    |       | 70    | 93    |       |       |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     |       | 41    | 64    |       |       |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3006**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Non-reversible     | -8    | 80    |       | 93    |       | 116   |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     | 88    |       | 101   |       | 124   |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Reversible         | -1    | 132   |       | 123   |       | 191   |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     | 133   |       | 124   |       | 192   |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| **SFCA3007**       |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Non-reversible     | 19    | 26    | 74    |       | 126   |       |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     | 7     | 55    |       | 107   |       |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| Reversible         | -15   | 141   | 138   |       | 196   |       |
|                    |       |       |       |       |       |       |
| Mean change, mL    | 0     | 156   | 153   |       | 211   |       |
|                    |       |       |       |       |       |       |
| Difference from    |       |       |       |       |       |       |
| placebo            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+

The sponsor also examined other efficacy endpoints for the
non-reversible and reversible subgroups. As noted above, the sponsor
presented integrated data from the three pivotal studies. These data are
discussed below.

The GAS of the CBSQ showed no clinically significant differences from
placebo for any treatment group in the non-reversible and reversible
groups. The GAS of the CBSQ was numerically favored in the reversible
group \[clinstat\\ise\\ise.pdf, page 215\].

Mean TDI scores showed clinically significant differences from placebo
for the non-reversible group for FP 500, SAL 50/FP 500, and SAL 50/FP
250. Mean TDI scores showed clinically significant differences from
placebo for current smokers for SAL 50/FP 250 and SAL 50/FP 500. TDI
scores numerically favored former smokers \[clinstat\\ise\\ise.pdf, page
217\].

The incidence of COPD exacerbations of any intensity and moderate or
severe COPD exacerbations for all active treatments was slightly higher
in the non-reversible subgroup than in the reversible subgroup. The
incidence of moderate or severe COPD exacerbations was slightly lower
for FP 500 and FP 250 in the reversible group than in the reversible
group. There was no difference in survival analyses for time to first
COPD exacerbation of any intensity or time to first moderate or severe
COPD exacerbation for FP 500 or FP 500 with regards to smoking status
\[clinstat\\ise\\ise.pdf, pages 218-219\].

The Overall score of the CRDQ, the health-related quality of life
instrument, showed no clinically significant differences from placebo
for any treatment group in both the non-reversible and reversible
groups. The Overall score of the CBSQ was numerically favored in the
reversible group \[clinstat\\ise\\ise.pdf, page 248\].

*[Reviewer comment:]{.underline}*

*These data suggest that patients who had an absolute volume increase
≥200 mL with baseline FEV~1~ reversibility of ≥12% had a greater
treatment effect from FP 500 and FP 250. The most prominent treatment
effects were noted for the primary efficacy endpoint, change in FEV~1~
from baseline at endpoint. Secondary efficacy endpoint results showed
smaller differences between the non-reversible and reversible groups.*

## Subgroup analyses, demographics

The sponsor provided subgroup analyses of efficacy by gender, race, and
age. These are reviewed below.

Males had greater absolute mean changes from baseline in FEV~1~ at
endpoint than women for all active treatment groups. Mean percent change
from baseline in FEV~1~ at endpoint was similar for men and women,
however, indicating the larger absolute mean change in men was due to
larger lung volumes \[clinstat\\ise\\ise.pdf, page 227\]. The mean
change from baseline in CBSQ GAS was similar in men and women for
treatment groups. Women had slightly greater TDI scores at endpoint than
men. Women in FP 500 and FP 250 groups had slightly more COPD
exacerbations than did men, but this observation was also present in the
placebo group. Women in the FP 500 and FP 250 groups had more slightly
more moderate or severe COPD exacerbations than men, when compared with
data for the placebo group \[clinstat\\ise\\ise.pdf, page 228-238\].

No consistent difference in mean change from baseline in FEV~1~ was
noted for all treatment groups when data for patients \<65 years and ≥65
years were compared. Changes in the CGSQ GAS were similar among
treatments for patients \<65 years and ≥65 years. Changes in TDI scores
were similar among treatments for patients \<65 years and ≥65 years.
Incidences of COPD exacerbations in the FP 500 and FP 250 groups
relative to placebo were higher for patients ≥65 years than those \<65
years. Incidences of COPD exacerbations in the FP 500 group relative to
placebo were higher for patients ≥65 years than those \<65 years
\[clinstat\\ise\\ise.pdf, page 233-240\].

As noted in each of the individual study reviews elsewhere in this
document, the vast majority of patients in this study were of Caucasian
race. There were few patients of Black or Asian race. Non-Caucasian
races represented 6% or less of each of the treatment groups. The small
number of Non-Caucasian patients makes it difficult to draw firm
conclusions. Mean percent change from baseline in FEV~1~ at endpoint by
race appeared to be greatest in patients of Other race, followed by
patients of Black race, with the smallest in Caucasian patients
\[clinstat\\ise\\ise.pdf, page 240\]. Changes in the CBSQ GAS appeared
to be similar among racial subgroups. COPD exacerbations and moderate or
severe COPD exacerbations appeared to be most frequent in patients of
Black race, followed by Caucasian patients, and lowest in patients of
Other race \[clinstat\\ise\\ise.pdf, page 241-246\].

*[Reviewer comments:]{.underline}*

*The under-representation of non-Caucasian patients in these studies is
problematic in that the sponsor has not adequately studied the efficacy
of FP in non-Caucasian patients with COPD. Additional information on the
efficacy of FP in a more racially diverse study population is
recommended. Safety data from future studies should be examined to
determine if the increases in COPD exacerbations in women and patients ≥
65 years represent true safety signals.*

## References

1.  American Thoracic Society. Standards for the diagnosis and care of
    patients with chronic obstructive pulmonary disease. Am J Respir
    Crit Care Med 1995;152:S77-S121.

2.  Barnes PJ. Chronic Obstructive Pulmonary Disease. New Engl J Med
    2000;343:269-280.

3.  The Lung Health Study Research Group. Effect of Inhaled
    Triamcinolone on the Decline in Pulmonary Function in Chronic
    Obstructive Pulmonary Disease. New Engl J Med 2000;343:1902-1909.

# Integrated review of safety

Integrated review of safety data supporting this application follows
below.

## Summary and conclusions

Safety data from the three pivotal studies in this application were
integrated in support of this application. These studies were
randomized, double-blind, placebo-controlled, parallel group,
multicenter trials that had a similar design and were conducted in a
similar manner. The studies were designed to evaluate the safety and
efficacy of SAL, FP, and the SAL/FP combination administered BID via the
Diskus over 24 weeks for the treatment of COPD. FP 250, FP 500, and
placebo were studied in FLTA3025. FP 500, SAL 50/FP 250, SAL 50, and
placebo were studied in SFCA3006. FP 250, SAL 50/FP 500, SAL 50, and
placebo were studied in SFCA 30007.

The majority of patients were males. Non-Caucasian patients were
seriously under-represented in these studies, representing approximately
5% of patients studied. . Approximately one third of patients had
dyspnea with walking on level ground for 100 yards or less. Drug
exposure was adequate to assess safety over the 24-week study period.

Adverse events (AEs) were fairly common in these studies. A dose
response effect was noted when comparing all AEs for placebo (69%) with
FP 250 (74%) and FP 500 (80%). AEs occurring at a frequency ≥3% and more
frequently with FP 250, FP 500, SAL 50/FP 250, or SAL 50/FP 500 than
with placebo included upper respiratory tract infection, headaches,
musculoskeletal pain, throat irritation, viral respiratory infections,
URI, candidiasis of the mouth or throat, nasal congestion/blockage,
cough, sinusitis, nausea and vomiting, hoarseness/dysphonia, fever,
malaise and fatigue, muscle cramps and spasms, rhinitis, dizziness,
hypertension, sinusitis/sinus infection, and muscle pain.

When comparing placebo with FP 250 and FP 500, a dose response effect
was noted for URTI, headaches, viral respiratory infections, URTI,
candidiasis of the mouth or throat, nasal congestion/blockage, and
muscle pain. Many of the AEs noted are also noted in the labels for
Flovent MDI and Flovent Rotadisk. AEs reported in these studies that are
not noted in current labeling for other Flovent products include
musculoskeletal pain, nausea and vomiting, airway irritation (throat
irritation, cough, rhinitis), dizziness, malaise and fatigue).
Differences could be attributed to differences in patient population or
in magnitude of the dose of FP, which was high for COPD (500 to 1000 mcg
per day) when compared to the asthmatic population (100 to up to 500 mcg
per day for moderate, persistent asthma; 500 to 1000 mcg per day for
oral corticosteroid sparing indication).

AEs associated with use of inhaled and systemic corticosteroids were
noted in these studies. Candidiasis, throat irritation, and
hoarseness/dysphonia were more common in FP 250, FP 500, SAL 50/FP 250,
and SAL 50/FP 500 than in placebo. A dose response effect for
candidiasis was seen when comparing placebo (1%) with FP 250 (7%) and FP
500 (13%). There were a small number of AEs for fractures, cataracts,
hyperglycemia, diabetes mellitus, and impaired glucose tolerance, and
the frequencies of these AEs were similar among treatment groups. There
was a higher frequency of pneumonia for FP 250 (1%), FP 500 (2%), and
SAL 50/FP 500 (1%) than for placebo (\<1%).

There were four deaths in placebo-treated patients in these studies.
There were no deaths in patients that received active treatment. There
was a higher frequency of SAEs due to COPD for FP 250 and FP 500, and a
suggestion of an association with SAEs due to pneumonia with FP
treatment.

Withdrawals due to any AE were more common in FP 500 and SAL 50/FP 500
than in placebo. Withdrawals due to AEs for COPD were more common in FP
500 and FP 250 than in placebo; a dose response effect was noted.
Withdrawals due to pneumonia were more common in FP 500, FP 250, and SAL
50/FP 500 than for placebo. Withdrawals due to candidiasis mouth/throat
only occurred in FP 500-treated patients.

Plasma cortisol levels were studied in FLTA3025. FP treatment groups had
lower mean cortisol AUC~12~ and mean C~min~ than the placebo group, with
a dose response effect noted. Mean cortisol AUC~12~ was 21% lower than
placebo for FP 500 and 10% lower than placebo for FP 250, indicating
dose-related systemic absorption and systemic activity from Flovent
Diskus. The plasma cortisol samples were taken at Week 4, early in the
study. Cosyntropin stimulation testing was performed in SFCA3006 and
SFCA3007 on a subset of patients (15 -- 20%). The data for cosyntropin
stimulation testing show no evidence of adrenal suppression, however,
cosyntropin stimulation testing is intended as a means to diagnose
adrenal insufficiency and is fairly insensitive as a measure of adrenal
suppression.

Subgroup analyses of safety endpoints in the pivotal studies in this
application reveal no gender effects associated with treatment group.
SAEs due to pneumonia were more common in patients ≤65 years of age who
were treated with FP 500 and SAL 50/FP 500. Withdrawals due to
pneumonias were more common in patients ≥65 years of age who were
treated with FP 500 and SAL 50/FP 500. The small number of non-Caucasian
patients did not allow for an analysis of AEs, SAEs, or withdrawals due
to AEs by race.

The sponsor also provided safety data from other studies to support this
application. These data included blinded listings of deaths and SAEs
from ongoing clinical studies, as well as safety information from
completed clinical pharmacology and clinical studies. Blinded listings
of deaths and SAEs from ongoing clinical studies provided no useful
safety information. Many AEs and SAEs from the completed studies are
similar to those that were noted in the three pivotal studies and those
noted in current labeling of Flovent product formulations. However, both
upper respiratory infections and lower respiratory infections, including
pneumonia, were more frequent in FP-treated patients than in placebo.
Patients treated with FP MDI 500 mcg BID over the 3-year course of
FLIT78 (also known as ISOLDE) had a higher frequency of events
associated with systemic effects of corticosteroids than patients
treated with placebo. These events included gastrointestinal hemorrhage,
diabetes mellitus, hyperglycemia, ocular pressure disorders, decreased
cortisol, abnormal adrenal hormone levels, Cushing's syndrome/symptoms,
hypofunction of the adrenal cortex, skin hemorrhage, acne and
folliculitis, and muscle atrophy, weakness, and tiredness. One patient
in FLIT98 was noted as having a SAE for decreased cortisol. FLTI98 was a
4-week randomized, double blind, placebo controlled study of FP MDI 1000
mcg BID in patients with COPD exacerbations.

These supportive studies also included laboratory data that showed
evidence of HPA-axis effects of inhaled FP. FLTA1003 was a open-label,
single dose, 4-way crossover, PK/PD study in normal subjects. Patients
received 1000 mcg of FP in four different dosage strengths of the Diskus
formulation. Compared to baseline, mean urinary cortisol excretion was
decreased by 42% to 62% in all treatment groups in this study, and many
individual patients had decreases in urinary cortisol excretion event
after the first dose of study treatment.

The sponsor studied effects on bone mineral density in two controlled,
long-term studies of FP in the treatment of asthma. These studies were
FLTA3001 and FLTA3017. Lumbar spine bone mineral density measurements in
FLTA3001 demonstrated no statistically different treatment effects at
24, 52, 76, and 104 weeks of double-blind treatment with placebo, FP MDI
88 mcg BID, or FP MDI 440 mcg BID. Lumbar spine bone mineral density
measurements in FLTA3017 demonstrated no statistically different
treatment effects at 24, 52, 76, and 104 weeks of double-blind treatment
with placebo or FP 500 mcg BID with the Rotadisk formulation. The lumbar
spine was the only area in these studies that underwent prospective
quality assurance from the osteoporosis central laboratory.
Unfortunately, results from the proximal femur, a more sensitive area
for corticosteroid effect, had no prospective quality assurance. These
studies were performed in a younger population of asthma patients, a
population that would be less sensitive to bone effects of
corticosteroids than older COPD patients would be.

The sponsor does not appear to have established the safety of FP in the
proposed population. The sponsor has not adequately studied the safety
of FP in non-Caucasian patients with COPD. Additional study of the
safety of FP in a more racially diverse study population is strongly
suggested. Further study is also required to demonstrate the safety of
this product in the COPD population, a population that would be at
higher risk for systemic corticosteroid effects. The pivotal studies
were likely to be of insufficient duration to detect differences between
treatment groups for uncommon events such as fractures, cataracts,
ocular pressure disorders, and disorders of glucose metabolism. The
pivotal studies were not designed to specifically look for cataracts or
systemic bone effects and exclusion criteria specifically selected
subjects with baseline bone or ocular problems. Safety data from
supportive studies raise concerns about a higher incidence of
respiratory infections, pneumonia, HPA axis effects, among others, in
FP-treated patients, and do not adequately address bone effects in the
proposed population.

The sponsor has recently started a 3-year study of FP 500 mcg BID, SAL
50/FP 500 BID, SAL 50 BID, and placebo BID via the Diskus formulation in
COPD patients (SCO30003). Bone density is to be evaluated over three
years in a subpopulation of 600 patients. This study will also assess
bone fractures and ocular events in the entire study population of 5000
patients. The long-term safety data that will be provided in this study
will be critical in assessing the long-term risk/benefit analysis for
this product in the proposed population.

### Content

The following data were reviewed in preparation of this overview of
safety:

-   Safety data from the following pivotal studies

```{=html}
<!-- -->
```
-   FLTA3025

-   SFCA3006

-   SFCA3007

```{=html}
<!-- -->
```
-   Supportive safety data from other studies

```{=html}
<!-- -->
```
-   AEs and HPA-axis data from clinical pharmacology study FLTA1003

-   Blinded listings of deaths and SAEs from ongoing clinical studies
    SFCB3024, SCO30003

-   Studies of Flovent MDI 500 mcg BID, FLIP63, FLIT78, FLIT97, FLIT98

-   Bone mineral density data from two long-term studies in asthma,
    FLTA3001 and FLTA3017

-   Blinded listings of deaths and SAEs from nine ongoing non-US studies
    used to support regional markets (SCO30001, SCO40002, SMS40026,
    SMS40130, SMS40308, SAM30001, FCO40003, FCO30002, and FCO40004)

The following data are reviewed in Dr. Gilbert-McClain's Medical Officer
Review of the application for the COPD indication for the Advair
product, NDA 21-077, S003.

-   Safety update, including postmarketing reports and a literature
    review

### Safety data from pivotal studies

A review of integrated safety data from the three pivotal clinical
studies in this application, FLTA3025, SFCA3006, and SFCA3007, follows
below.

### Description of pivotal studies

This application included three pivotal clinical studies, FLTA3025,
SFCA3006, and SFCA3007. These studies were randomized, double-blind,
placebo-controlled, parallel group, multicenter trials that had a
similar design and were conducted in a similar manner. The studies were
designed to evaluate the safety and efficacy of SAL, FP, and the SAL/FP
combination administered BID via the Diskus over 24 weeks for the
treatment of COPD. These studies are summarized in Table 7.1.
\[clinstat\\iss\\iss.pdf, page 33\].

Table 7.1. Summary of pivotal studies in this application, NDA 20-833,
S004.

+-------+-----+--------------------+-------+---------+------+-------+
| Study | St  | Treatment groups   | Dur   | Design  | Nu   | Diagn |
| n     | udy |                    | ation |         | mber | osis, |
| umber | t   |                    | of    |         | of   | age   |
|       | ype |                    | trea  |         | pati | of    |
|       |     |                    | tment |         | ents | sub   |
|       |     |                    |       |         |      | jects |
+=======+=====+====================+=======+=========+======+=======+
| FLT   | Ef  | FP 250 mcg Diskus  | 24    | Rand    | 640  | COPD, |
| A3025 | fic | BID                | weeks | omized, |      |       |
|       | acy |                    |       | double  |      | ≥40   |
|       | and | FP 500 mcg Diskus  |       | -blind, |      | years |
|       | saf | BID                |       | placebo |      |       |
|       | ety |                    |       | cont    |      |       |
|       |     | Placebo Diskus BID |       | rolled, |      |       |
|       |     |                    |       | p       |      |       |
|       |     |                    |       | arallel |      |       |
|       |     |                    |       | group   |      |       |
+-------+-----+--------------------+-------+---------+------+-------+
| SFC   | Ef  | SAL 50 mcg Diskus  | 24    | Rand    | 640  | COPD, |
| A3006 | fic | BID                | weeks | omized, |      |       |
|       | acy |                    |       | double  |      | ≥40   |
|       | and | FP 500 mcg Diskus  |       | -blind, |      | years |
|       | saf | BID                |       | placebo |      |       |
|       | ety |                    |       | cont    |      |       |
|       |     | SAL 50 mcg/FP 500  |       | rolled, |      |       |
|       |     | mcg Diskus BID     |       | p       |      |       |
|       |     |                    |       | arallel |      |       |
|       |     | Placebo Diskus BID |       | group   |      |       |
+-------+-----+--------------------+-------+---------+------+-------+
| SFC   | Ef  | SAL 50 mcg Diskus  | 24    | Rand    | 640  | COPD, |
| A3007 | fic | BID                | weeks | omized, |      |       |
|       | acy |                    |       | double  |      | ≥40   |
|       | and | FP 250 mcg Diskus  |       | -blind, |      | years |
|       | saf | BID                |       | placebo |      |       |
|       | ety |                    |       | cont    |      |       |
|       |     | SAL 50 mcg/FP 250  |       | rolled, |      |       |
|       |     | mcg Diskus BID     |       | p       |      |       |
|       |     |                    |       | arallel |      |       |
|       |     | Placebo BID        |       | group   |      |       |
+-------+-----+--------------------+-------+---------+------+-------+

Integrated review of safety findings from these three pivotal studies
follow.

#### Demographics

Patient demographics and baseline characteristics for the pivotal
studies in this application are presented in Table 7.2. The mean age of
patients was fairly similar in each of the treatment groups,
approximately 62 to 64 years. Patients ranged from 39 to 90 years of
age.

The majority of patients in these studies were of male gender. Males
represented from 61% to 70% of patients in each of the treatment groups.
The distribution of male and female patients was fairly similar in each
of the treatment groups. The vast majority of patients in these studies
were of Caucasian race, approximately 95%. There were very few patients
of Black or Asian race. Non-Caucasian races represented less than 6% of
most treatment groups, with the greatest proportion of Non-Caucasian
patients in the FP 250 group (7%, 28/399).

With regard to symptoms, all patients experienced dyspnea with walking
on level ground, and approximately one third of the patients in each of
the treatment groups had dyspnea with walking on level ground for 100
yards or less (MMRC Dyspnea Score ≥3). The majority of patients were
former smokers, but a fairly large minority of patients were current
smokers. Mean history of smoking was approximately 60 pack-years in each
of the treatment groups, much larger than the 20 pack-year history
required for entry into the studies. Approximately 30% of each of the
treatment groups were using corticosteroids at the time of screening.
Use of inhaled corticosteroids at the time of screening ranged from 23%
(SAL50/FP 250) to 29% (FP 250).

*[Reviewer comments:]{.underline}*

*The under-representation of non-Caucasian patients in these studies is
a serious deficiency. The degree of dyspnea, duration of COPD, smoking
status, and magnitude of smoking history were fairly similar among
treatment groups. The population studied is characterized by long
smoking histories, significant dyspnea, and longstanding COPD.*

*A fairly large minority of patients was taking inhaled corticosteroids
at the time of screening. One would expect these patients to more likely
to be corticosteroid-responsive than those not taking inhaled
corticosteroids, as one would expect patients with no response or a poor
response to have their treatment discontinued. Patients with inhaled
corticosteroid use were evenly distributed between treatment groups.*

> Table 7.2. Summary of patient demographics and baseline
> characteristics of this application, NDA 20-833, S004
> \[clinstat\\iss\\iss.pdf, page 41\].

+---------+---------+---------+---------+---------+---------+---------+
| **Ch    | **Pl    | **SAL   | **FP    | **FP    | **SAL   | **SAL   |
| aracter | acebo** | 50**    | 250**   | 500**   | 50/FP   | 50/FP   |
| istic** |         |         |         |         | 250**   | 500**   |
|         | **N =   | **N =   | **N =   | **N =   |         |         |
|         | 576**   | 341**   | 399**   | 391**   | **N =   | **N =   |
|         |         |         |         |         | 178**   | 169**   |
+=========+=========+=========+=========+=========+=========+=========+
| **Age,  | **n     | **n     | **n     | **n     | **n     | **n     |
| years** | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   |
+---------+---------+---------+---------+---------+---------+---------+
| Mean    | 64.6    | 63.9    | 64.4    | 63.7    | 63.4    | 62.0    |
| age     |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Range   | 40 --   | 40 --   | 40 --   | 39 --   | 40 --   | 40 --   |
|         | 90      | 87      | 88      | 85      | 87      | 86      |
+---------+---------+---------+---------+---------+---------+---------+
|         |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **G     | **n     | **n     | **n     | **n     | **n     | **n     |
| ender** | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   |
+---------+---------+---------+---------+---------+---------+---------+
| Female  | 171     | 133     | 122     | 141     | 70 (39) | 64 (38) |
|         | (30)    | (39)    | (31)    | (36)    |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Male    | 405     | 208     | 277     | 250     | 108     | 105     |
|         | (70)    | (61)    | (69)    | (64)    | (61)    | (62)    |
+---------+---------+---------+---------+---------+---------+---------+
|         |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| *       | **n     | **n     | **n     | **n     | **n     | **n     |
| *Race** | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   |
+---------+---------+---------+---------+---------+---------+---------+
| Ca      | 539     | 321     | 371     | 367     | 170     | 159     |
| ucasian | (94)    | (94)    | (93)    | (94)    | (96)    | (94)    |
+---------+---------+---------+---------+---------+---------+---------+
| Black   | 23 (4)  | 13 (4)  | 18 (5)  | 17 (4)  | 5 (3)   | 7 (4)   |
+---------+---------+---------+---------+---------+---------+---------+
| Asia    | 14 (2)  | 7 (2)   | 10 (3)  | 7 (2)   | 3 (2)   | 3 (2)   |
| n/Other |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
|         |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **MMRC  | **n     | **n     | **n     | **n     | **n     | **n     |
| Dyspnea | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   |
| Score** |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| 2       | 385     | 211     | 257     | 253     | 109     | 108     |
|         | (67)    | (62)    | (64)    | (65)    | (61)    | (64)    |
+---------+---------+---------+---------+---------+---------+---------+
| 3       | 168     | 113     | 133     | 120     | 63 (35) | 59 (35) |
|         | (29)    | (33)    | (33)    | (31)    |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| 4       | 23 (4)  | 17 (5)  | 7 (2)   | 18 (5)  | 6 (3)   | 2 (1)   |
+---------+---------+---------+---------+---------+---------+---------+
| Missing | 0 (0)   | 0 (0)   | 2 (1)   | 0 (0)   | 0 (0)   | 0 (0)   |
+---------+---------+---------+---------+---------+---------+---------+
|         |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **      | **n     | **n     | **n     | **n     | **n     | **n     |
| Smoking | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   |
| s       |         |         |         |         |         |         |
| tatus** |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Former  | 303     | 175     | 214     | 208     | 101     | 91 (54) |
| smoker  | (53)    | (51)    | (54)    | (53)    | (57)    |         |
+---------+---------+---------+---------+---------+---------+---------+
| Current | 273     | 166     | 185     | 183     | 77 (43) | 78 (46) |
| smoker  | (47)    | (49)    | (46)    | (47)    |         |         |
+---------+---------+---------+---------+---------+---------+---------+
|         |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Pac   |         |         |         |         |         |         |
| k-years |         |         |         |         |         |         |
| s       |         |         |         |         |         |         |
| moked** |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Mean    | 62.7    | 63.2    | 60.5    | 60.1    | 59.8    | 62.1    |
+---------+---------+---------+---------+---------+---------+---------+
| Range   | 20 --   | 20-224  | 20-162  | 20-201  | 20-220  | 15-150  |
|         | 168     |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
|         |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **      | **n     | **n     | **n     | **n     | **n     | **n     |
| Inhaled | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   | (%)**   |
| s       |         |         |         |         |         |         |
| teroids |         |         |         |         |         |         |
| at      |         |         |         |         |         |         |
| scre    |         |         |         |         |         |         |
| ening** |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Yes     | 153     | 84 (25) | 117     | 111     | 41 (23) | 48 (28) |
|         | (27)    |         | (29)    | (28)    |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| No      | 423     | 257     | 282     | 280     | 137     | 121     |
|         | (73)    | (75)    | (71)    | (72)    | (77)    | (72)    |
+---------+---------+---------+---------+---------+---------+---------+
|         |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+

#### Disposition

Patient disposition for the pivotal studies in this application is
presented in Table 7.3. There were a total of 2054 patients randomized
and 1365 patients completed the studies. There were 689 patients that
discontinued prematurely for an overall dropout rate of 33.5%. The
largest percentage of discontinuations was in the FP 500 group (37%,
143/391). The smallest percentage of discontinuations was in the SAL 50
(30%, 103/341) and SAL 50/FP 250 (30%, 53/178) treatment groups.
Although more of an efficacy than safety issue, it is notable that there
is little if any difference in dropout rate between the active treatment
groups and placebo, unlike what is typically observed in asthma trials
using inhaled corticosteroids.

The most frequent reason for discontinuation for all groups was COPD
exacerbation, which ranged from 25% in the SAL 50 and FAL 50/FP 500
groups to 30% in the placebo group. Adverse events (AEs) leading to
discontinuation were most common in the FP 500 group (27%, 39/341) and
least in the SAL 50, FP 250, and SAL 50/FP 250 groups (all 17%). Lack of
efficacy as a reason for discontinuation was most frequent in the FP 250
(19%) and least frequent in the FP 500 and SAL 50/FP 500 groups (5%).
Protocol violations were also more frequent in the FP 500 group (20%)
compared with the other treatment groups (13% to 18%)
\[clinstat\\iss\\iss.pdf, page 49\].

*[Reviewer comment:]{.underline}*

*Although discontinuations due to lack of efficacy occurred at low
frequency in the FP 500 group, this group also had the highest frequency
of discontinuation due to AEs of all the treatment groups.*

Table 7.3. Patient disposition, pivotal studies in this application, NDA
20-833, S004 \[clinstat\\iss\\iss.pdf, page 50\]

+------------+--------+--------+--------+--------+--------+--------+
|            | **Pla  | **SAL  | **FP   | **FP   | **SAL  | **SAL  |
|            | cebo** | 50**   | 250**  | 500**  | 50/FP  | 50/FP  |
|            |        |        |        |        | 250**  | 500**  |
|            | **N    | **N    | **N    | **N    |        |        |
|            | (%)**  | (%)**  | (%)**  | (%)**  | **N    | **N    |
|            |        |        |        |        | (%)**  | (%)**  |
+============+========+========+========+========+========+========+
| Patients   | 576    | 341    | 399    | 391    | 178    | 169    |
| randomized | (100)  | (100)  | (100)  | (100)  | (100)  | (100)  |
+------------+--------+--------+--------+--------+--------+--------+
| Patients   | 367    | 238    | 273    | 248    | 125    | 114    |
| completed  | (64)   | (70)   | (68)   | (63)   | (70)   | (67)   |
+------------+--------+--------+--------+--------+--------+--------+
| Patients   | 209    | 103    | 126    | 143    | 53     | 55     |
| di         | (36)   | (30)   | (32)   | (37)   | (30)   | (33)   |
| scontinued |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Reason     |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Adverse    | 38     | 17     | 22     | 39     | 9 (17) | 11     |
| event      | (18)   | (17)   | (17)   | (27)   |        | (20)   |
+------------+--------+--------+--------+--------+--------+--------+
| COPD       | 62     | 26     | 35     | 39     | 15     | 14     |
| ex         | (30)   | (25)   | (28)   | (27)   | (28)   | (25)   |
| acerbation |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Withdrawn  | 29     | 13     | 7 (6)  | 13 (9) | 10     | 11     |
| consent    | (14)   | (13)   |        |        | (19)   | (20)   |
+------------+--------+--------+--------+--------+--------+--------+
| Lack of    | 35     | 16     | 24     | 7 (5)  | 3 (6)  | 3 (5)  |
| efficacy   | (17)   | (16)   | (19)   |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Lost to    | 5 (2)  | 4 (4)  | 8 (6)  | 7 (5)  | 6 (11) | 2 (4)  |
| follow-up  |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Protocol   | 27     | 18     | 23     | 29     | 7 (13) | 8 (15) |
| violation  | (13)   | (17)   | (18)   | (20)   |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Other      | 13 (6) | 9 (9)  | 7 (6)  | 9 (6)  | 3 (6)  | 6 (11) |
+------------+--------+--------+--------+--------+--------+--------+

#### Exposure

Total drug exposure is summarized in Table 7.4. Approximately more than
50% of each group completed ≥24 weeks of study treatment. The mean
duration of treatment was 128.9 days for placebo, 135.6 days for FP 250,
and 131.9 days for FP 250.

Table 7.4. Total drug exposure, pivotal studies in this application, NDA
20-833, S004 \[clinstat\\iss\\iss.pdf, page 58\].

+----------+--------+--------+--------+--------+---------+---------+
| **       | **Pla  | **SAL  | **FP   | **FP   | **SAL   | **SAL   |
| Duration | cebo** | 50**   | 250**  | 500**  | 50/FP   | 50/FP   |
| of       |        |        |        |        | 250**   | 500**   |
| tre      | **N =  | **N =  | **N =  | **N =  |         |         |
| atment** | 576**  | 341**  | 399**  | 391**  | **N =   | **N =   |
|          |        |        |        |        | 178**   | 169**   |
|          | **n    | **n    | **n    | **n    |         |         |
|          | (%)**  | (%)**  | (%)**  | (%)**  | **n     | **N     |
|          |        |        |        |        | (%)**   | (%)**   |
+==========+========+========+========+========+=========+=========+
| 0 to \<4 | 78     | 34     | 35 (9) | 36 (9) | 15 (8)  | 16 (9)  |
| weeks    | (14)   | (10)   |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| 4 to \<8 | 36 (6) | 17 (5) | 27 (7) | 27 (7) | 5 (3)   | 10 (6)  |
| weeks    |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| 8 to     | 26 (5) | 18 (5) | 21 (5) | 24 (6) | 10 (6)  | 6 (4)   |
| \<12     |        |        |        |        |         |         |
| weeks    |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| 12 to    | 33 (6) | 7 (2)  | 15 (4) | 28 (7) | 7 (4)   | 5 (3)   |
| \<16     |        |        |        |        |         |         |
| weeks    |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| 16 to    | 24 (4) | 13 (4) | 21 (5) | 19 (5) | 10 (6)  | 9 (5)   |
| \<20     |        |        |        |        |         |         |
| weeks    |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| 20 to    | 64     | 35     | 59     | 38     | 19 (11) | 23 (14) |
| \<24     | (11)   | (10)   | (15)   | (10)   |         |         |
| weeks    |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| ≥24      | 315    | 217    | 221    | 219    | 112     | 100     |
| weeks    | (55)   | (64)   | (55)   | (56)   | (63)    | (59)    |
+----------+--------+--------+--------+--------+---------+---------+
| T        | 128.9  | 138.5  | 135.6  | 131.9  | 141.3   | 137.8   |
| reatment |        |        |        |        |         |         |
| days,    |        |        |        |        |         |         |
| mean     |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+

*[Reviewer comment:]{.underline}*

*Drug exposure appears to be adequate to allow for assessment of safety
over the 24-week treatment period, given the recognition that compliance
reporting is commonly unreliable, but should not be taken as supportive
of the adequacy of safety assessment in the long-term.*

#### Adverse events

Adverse events (AEs) were fairly common in these studies. AEs occurring
at a frequency of ≥3% and more frequently in FP 250, FP 500, SAL 50/FP
250, or SAL 50/FP 500 than placebo are summarized in Table 7.5. A dose
response effect was noted when comparing all AEs for placebo (69%) with
FP 250 (74%) and FP 500 (80%). A dose response effect was noted when
comparing all AEs for placebo (69%) with SAL 50/FP 250 (70%) and SAL
50/FP 500 (78%).

AEs occurring at a frequency ≥3% and more frequently with FP 250, FP
500, SAL 50/FP 250, or SAL 50/FP 500 than with placebo included upper
respiratory tract infection, headaches, musculoskeletal pain, throat
irritation, viral respiratory infections, URI, candidiasis of the mouth
or throat, nasal congestion/blockage, cough, sinusitis, nausea and
vomiting, hoarseness/dysphonia, fever, malaise and fatigue, muscle
cramps and spasms, rhinitis, dizziness, hypertension, sinusitis/sinus
infection, and muscle pain \[clinstat\\iss\\iss.pdf, page 67\].

When comparing placebo with FP 250 and FP 500, a dose response effect
was noted for URTI, headaches, viral respiratory infections, URTI,
candidiasis of the mouth or throat, nasal congestion/blockage, and
muscle pain \[clinstat\\iss\\iss.pdf, page 67\].

When comparing placebo with SAL 50/FP 250 and SAL 50/FP 500, a dose
response effect was noted for headaches, throat irritation, viral
respiratory infections, sinusitis/sinus infection, and muscle cramps and
spasms \[clinstat\\iss\\iss.pdf, page 67\].

*[Reviewer comment:]{.underline}*

*Many of these AEs are noted in the labels for Flovent MDI and Flovent
Rotadisk. These include upper respiratory tract infection, headaches,
candidiasis, viral respiratory infections, nasal congestion, dysphonia,
sinusitis, diarrhea, and rhinitis. AEs reported in these studies that
are not noted in current labeling for other Flovent products include
musculoskeletal pain, nausea and vomiting, airway irritation (throat
irritation, cough, rhinitis), dizziness, malaise and fatigue.*

**Table 7.5. Adverse events occurring at a frequency of **3% and more
frequently in FP 250, FP 500, SAL 50/FP 250, or SAL 50/FP 500 than in
placebo, pivotal studies in this application, NDA 20-833, S004. Entries
represent number (percent) of patients \[clinstat\\iss\\iss.pdf, page
68\].

+----------+--------+--------+--------+--------+---------+---------+
| *        | **Pla  | **SAL  | **FP   | **FP   | **SAL   | **SAL   |
| *Adverse | cebo** | 50**   | 250**  | 500**  | 50/FP   | 50/FP   |
| event**  |        |        |        |        | 250**   | 500**   |
|          | **N =  | **N =  | **N =  | **N =  |         |         |
|          | 576**  | 341**  | 399**  | 391**  | **N =   | **N =   |
|          |        |        |        |        | 178**   | 169**   |
|          | **n    | **n    | **n    | **n    |         |         |
|          | (%)**  | (%)**  | (%)**  | (%)**  | **n     | **n     |
|          |        |        |        |        | (%)**   | (%)**   |
+----------+--------+--------+--------+--------+---------+---------+
| Any      | 397    | 233    | 294    | 312    | 124     | 131     |
| event    | (69)   | (68)   | (74)   | (80)   | (70)    | (78)    |
+----------+--------+--------+--------+--------+---------+---------+
| URTI\*   | 114    | 53     | 84     | 96     | 26 (15) | 43 (25) |
|          | (20)   | (16)   | (21)   | (25)   |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| H        | 66     | 47     | 51     | 65     | 28 (16) | 30 (18) |
| eadaches | (11)   | (14)   | (13)   | (17)   |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Musculo  | 58     | 42     | 41     | 35 (9) | 16 (9)  | 20 (12) |
| skeletal | (10)   | (12)   | (10)   |        |         |         |
| pain     |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Throat   | 36 (6) | 24 (7) | 35 (9) | 36 (9) | 15 (8)  | 19 (11) |
| ir       |        |        |        |        |         |         |
| ritation |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Viral    | 23 (4) | 17 (5) | 20 (5) | 36 (9) | 10 (6)  | 14 (8)  |
| res      |        |        |        |        |         |         |
| piratory |        |        |        |        |         |         |
| in       |        |        |        |        |         |         |
| fections |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Can      | 4      | 6 (2)  | 23 (6) | 46     | 17 (10) | 12 (7)  |
| didiasis | (\<1)  |        |        | (12)   |         |         |
| mout     |        |        |        |        |         |         |
| h/throat |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Nasal    | 19 (3) | 12 (4) | 17 (4) | 26 (7) | 5 (3)   | 7 (4)   |
| con      |        |        |        |        |         |         |
| gestion/ |        |        |        |        |         |         |
| blockage |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Cough    | 24 (4) | 17 (5) | 18 (5) | 15 (4) | 2 (1)   | 6 (4)   |
+----------+--------+--------+--------+--------+---------+---------+
| Si       | 24 (4) | 20 (6) | 30 (8) | 19 (5) | 9 (5)   | 12 (7)  |
| nusitis/ |        |        |        |        |         |         |
| sinus    |        |        |        |        |         |         |
| infec    |        |        |        |        |         |         |
| tion\*\* |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Nausea & | 18 (3) | 11 (3) | 16 (4) | 16 (4) | 4 (2)   | 6 (4)   |
| vomiting |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Hoa      | 6 (1)  | 2 \<1) | 18 (5) | 19 (5) | 9 (5)   | 5 (3)   |
| rseness/ |        |        |        |        |         |         |
| d        |        |        |        |        |         |         |
| ysphonia |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Fever    | 18 (3) | 4 (1)  | 12 (3) | 11 (3) | 8 (4)   | 6 (4)   |
+----------+--------+--------+--------+--------+---------+---------+
| Malaise  | 17 (3) | 7 (2)  | 11 (3) | 12 (3) | 6 (3)   | 6 (4)   |
| &        |        |        |        |        |         |         |
| fatigue  |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Muscle   | 7 (1)  | 10 (3) | 9 (2)  | 8 (2)  | 6 (3)   | 13 (8)  |
| cramps & |        |        |        |        |         |         |
| spasms   |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Rhinitis | 14 (2) | 12 (4) | 11 (3) | 8 (2)  | 4 (2)   | 3 (2)   |
+----------+--------+--------+--------+--------+---------+---------+
| D        | 10 (2) | 12 (4) | 7 (2)  | 7 (2)  | 7 (4)   | 5 (3)   |
| izziness |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Hype     | 11 (2) | 12 (4) | 5 (1)  | 9 (2)  | 4 (2)   | 5 (3)   |
| rtension |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Muscle   | 5      | 4 (1)  | 7 (2)  | 13 (3) | 0 (0)   | 7 (4)   |
| pain     | (\<1)  |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+

\*Combines sponsor's numbers for URTI and URI

\*\*Combines sponsor's numbers for sinusitis and sinusitis/sinus
infection

A listing of AEs that have been attributed to local and systemic effects
of corticosteroids is found in Table 7.6. With the exception of
oropharyngeal candidiasis, small numbers of these AEs were observed.
Candidiasis, throat irritation, and hoarseness/dysphonia were more
common in FP 250, FP 500, SAL 50/FP 250, and SAL 50/FP 500 than in
placebo. A dose response effect for candidiasis was seen when comparing
placebo (1%) with FP 250 (7%) and FP 500 (13%). A dose response effect
was seen for throat irritation when comparing placebo (6%) with SAL
50/FP 250 (8%) and SAL 50/FP 500 (11%) \[clinstat\\iss\\iss.pdf, pages
68, 275-307\]. There were a small number of AEs for fractures,
cataracts, hyperglycemia, diabetes mellitus, and impaired glucose
tolerance, and the frequencies of these AEs were similar among treatment
groups. There appeared to be higher frequency of pneumonia for FP 250
(1%), FP 500 (2%), and SAL 50/FP 500 (1%) than for placebo (\<1%).

Table 7.6. Selected adverse events of low frequency, pivotal studies in
this application, NDA 20-833, S004. Entries represent number (percent)
of patients \[clinstat\\iss\\iss.pdf, pages 68, 275-307\].

+----------+--------+--------+--------+--------+---------+---------+
| *        | **Pla  | **SAL  | **FP   | **FP   | **SAL   | **SAL   |
| *Adverse | cebo** | 50**   | 250**  | 500**  | 50/FP   | 50/FP   |
| event**  |        |        |        |        | 250**   | 500**   |
|          | **N =  | **N =  | **N =  | **N =  |         |         |
|          | 576**  | 341**  | 399**  | 391**  | **N =   | **N =   |
|          |        |        |        |        | 178**   | 169**   |
|          | **n    | **n    | **n    | **n    |         |         |
|          | (%)**  | (%)**  | (%)**  | (%)**  | **n     | **n     |
|          |        |        |        |        | (%)**   | (%)**   |
+==========+========+========+========+========+=========+=========+
| Any      | 397    | 233    | 294    | 312    | 124     | 131     |
| event    | (69)   | (68)   | (74)   | (80)   | (70)    | (78)    |
+----------+--------+--------+--------+--------+---------+---------+
| Candi    | 6 (1)  | 8 (2)  | 29 (7) | 50     | 20 (11) | 18 (11) |
| diasis\* |        |        |        | (13)   |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Throat   | 36 (6) | 24 (7) | 35 (9) | 36 (9) | 15 (8)  | 19 (11) |
| ir       |        |        |        |        |         |         |
| ritation |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| F        | 9 (2)  | 1      | 4 (1)  | 4 (1)  | 3 (2)   | 3 (2)   |
| ractures |        | (\<1)  |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| C        | 1      | 0 (0)  | 0 (0)  | 3      | 0 (0)   | 0 (0)   |
| ataracts | (\<1)  |        |        | (\<1)  |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Ocular   | 2      | 0 (0)  | 0 (0)  | 0 (0)  | 0 (0)   | 2 (1)   |
| pressure | (\<1)  |        |        |        |         |         |
| d        |        |        |        |        |         |         |
| isorders |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Hoa      | 6 (1)  | 2      | 18 (5) | 19 (5) | 9 (5)   | 5 (3)   |
| rseness/ |        | (\<1)  |        |        |         |         |
| d        |        |        |        |        |         |         |
| ysphonia |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| P        | 4      | 1      | 5 (1)  | 7 (2)  | 0 (0)   | 2 (1)   |
| neumonia | (\<1)  | (\<1)  |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Hyper    | 1      | 4      | 4 (1)  | 2      | 1 (\<1) | 1 (\<1) |
| glycemia | (\<1)  | (\<1)  |        | (\<1)  |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Diabetes | 1      | 0 (0)  | 0 (0)  | 1      | 0 (0)   | 2 (1)   |
| mellitus | (\<1)  |        |        | (\<1)  |         |         |
+----------+--------+--------+--------+--------+---------+---------+
| Impaired | 0 (0)  | 0 (0)  | 0 (0)  | 1      | 0 (0)   | 0 (0)   |
| glucose  |        |        |        | (\<1)  |         |         |
| t        |        |        |        |        |         |         |
| olerance |        |        |        |        |         |         |
+----------+--------+--------+--------+--------+---------+---------+

\*Includes candidiasis mouth/throat, candidiasis unspecified, and
unspecified oropharyngeal plaques.

*[Reviewer comment:]{.underline}*

*The large doses of FP used is underscored by the high frequency of
candidiasis in the FP 500 (13%) and SAL 50/FP 500 groups (11%) in these
6-month studies. There appears to be an association of pneumonia with
FP-treated patients. There is no signal for fractures, cataracts, ocular
pressure disorders, and disorders of glucose metabolism in these 6-month
studies. It is likely that these studies were of insufficient duration
to detect differences between treatment groups for these uncommon
events. Furthermore, these studies were not designed to specifically
look for cataract or systemic bone effects, both known to be associated
with systemic effects of corticosteroids. Ophthalmologic examination and
studies to assess osteoporosis would have been helpful to address these
concerns. There appears to be suggestion that pneumonia may be
associated with FP.*

#### Deaths

There were four deaths that occurred in patients in the pivotal clinical
studies in this application. All four deaths occurred in patients
treated with placebo. One of these four patients died after completing
study FLTA3025, three of these deaths occurred during SFCA3006. There
were no deaths in SFCA3007 \[clinstat\\iss\\iss.pdf.83-84\].

#### Serious adverse events

A total of 115 patients (6%, 115/2054) experienced SAEs during the
treatment period of these studies. The frequency of SAEs was similar
among treatment groups and ranged from 4% for SAL 50 and SAL 50/FP 250
to 7% for FP 500. SAEs occurring in more than one patient in any
treatment group are summarized in Table 7.7.

Table 7.7. SAEs occurring in more than one patient in any treatment
group, pivotal studies in this application, NDA 20-833, S004. Entries
represent number (percent) of patients \[clinstat\\iss\\iss.pdf, pages
84, 424-432\].

+---------+---------+---------+---------+---------+---------+---------+
| **SAE** | **Pl    | **SAL   | **FP    | **FP    | **SAL   | **SAL   |
|         | acebo** | 50**    | 250**   | 500**   | 50/FP   | 50/FP   |
|         |         |         |         |         | 250**   | 500**   |
|         | **N =   | **N =   | **N =   | **N =   |         |         |
|         | 576**   | 341**   | 399**   | 391**   | **N =   | **N =   |
|         |         |         |         |         | 178**   | 169**   |
+=========+=========+=========+=========+=========+=========+=========+
| Any SAE | 34 (6)  | 12 (4)  | 25 (6)  | 27 (7)  | 8 (4)   | 9 (5)   |
+---------+---------+---------+---------+---------+---------+---------+
| COPD    | 7 (1)   | 4 (1)   | 8 (2)   | 11 (3)  | 0 (0)   | 2 (1)   |
+---------+---------+---------+---------+---------+---------+---------+
| Pn      | 1 (\<1) | 1 (\<1) | 3 (\<1) | 4 (1)   | 0 (0)   | 2 (1)   |
| eumonia |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Chest   | 5 (\<1) | 1 (\<1) | 0 (0)   | 0 (0)   | 1 (\<1) | 2 (1)   |
| s       |         |         |         |         |         |         |
| ymptoms |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Fr      | 1 (\<1) | 0 (0)   | 2 (\<1) | 2 (\<1) | 1 (\<1) | 0 (0)   |
| actures |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Choleli | 1 (\<1) | 0 (0)   | 2 (\<2) | 0 (0)   | 0 (0)   | 0 (0)   |
| thiasis |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Syncope | 0 (0)   | 0 (0)   | 0 (0)   | 0 (0)   | 0 (0)   | 0 (0)   |
+---------+---------+---------+---------+---------+---------+---------+
| Dep     | 2 (\<1) | 0 (0)   | 0 (0)   | 0 (0)   | 0 (0)   | 0 (0)   |
| ressive |         |         |         |         |         |         |
| di      |         |         |         |         |         |         |
| sorders |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+

SAEs for COPD were more common in FP 250 and FP 500 than for placebo. A
dose response effect was noted for COPD. There was a suggestion that
SAEs for pneumonia were associated with FP.

*[Reviewer comment:]{.underline}*

*There was a higher frequency of COPD in FP 250 and FP 500, and a
suggestion of an association with pneumonia with FP. Although these may
be a chance occurrence, these data raise the concern that lower
respiratory tract infections may be associated with FP. It should be
noted that AEs for URTI were associated with FP in these studies, and
are noted in current FP labeling.*

#### Withdrawals due to AEs

Withdrawals due to any AE were more common in FP 500 (11%, 42/391) and
SAL 50/FP 500 (7%, 11/169) than in placebo (6%, 36/576). Withdrawals due
to AEs for COPD were more common in FP 500 (3%, 10/391) and FP 250 (2%,
8/399) than placebo (1%, 8/576); a dose response effect was noted.
Withdrawals due to pneumonia were more common in FP 500 (1%, 4/391), FP
250 (1%, 4/399), and SAL 50/FP 500 (1%, 2/169) than for placebo (\<1%,
1/576). Withdrawals due to candidiasis mouth/throat only occurred in FP
500-treated patients (\<1%, 3/391). Withdrawals due to viral respiratory
infections occurred only in FP 500 (\<1%, 1/391), FP 250 (\<1%, 1/399),
and SAL 50/FP 250 (\<1%, 1/178). Data for other withdrawals due to AEs
do not suggest any safety signal.

*[Reviewer comment:]{.underline}*

*Withdrawals due to AEs also suggest that lower respiratory tract and
viral infections may be associated with FP treatment in this population.
Withdrawals due to candidiasis mouth/throat only occurred in FP
500-treated patients, which underscores the large dose of FP used and is
concordant with other AE data from these pivotal studies.*

#### Vital signs

The sponsor did not provide an integrated summary of vital signs results
from the pivotal studies. The following is an integrated summary of this
reviewer's analysis of vital signs results from the pivotal studies.

There were no clinically significant changes from baseline in median
values of vital signs for any of the treatment groups in the pivotal
studies in this application \[clinstat\\copd\\flta3025.pdf, pages 147,
903-905; clinstat\\copd\\sfca3006.pdf, pages 1521-1520;
clinstat\\copd\\sfca3007.pdf, pages 999-1004\].

The sponsor provided a summary of 12-hour serial vital signs results
from SFCA3006 in their Integrated Safety Summary. These results are
pertinent to the SAL50, SAL 50/FP 250, and SAL 50/FP 500 products, and
not the FP 250 and FP 500 products. Accordingly these data are not
summarized in this section of this review.

#### Physical examination

Physical examinations were performed at Screening and at the Week 24
visit or the Discontinuation visit in each of these studies. Data were
recorded on subject progress notes, but not on case report forms (CRFs).
Physical examination abnormalities were recorded as AEs on the CRFs, but
no summary of physical examinations was provided \[NDA 20-833, SE1-004,
BM, 9/17/01, page 3\]. Any physical exam abnormalities are therefore
included in the AE section each pivotal study, and are also included in
the AE section of this safety summary.

#### Laboratory studies

Clinical laboratory tests were performed on samples collected at
screening, Week 12, and Week 24 and/or the Discontinuation visit for
each of the pivotal studies. Laboratory studies analyzed as safety
endpoints included hematology studies and blood chemistry studies.

Small numbers of patients in the pivotal studies had shifts in %
lymphocyte, % neutrophils, and WBC counts from baseline at Weeks 12 and
24 (\<1% to 7%). Larger numbers of patients had shifts in lymphocyte, %
neutrophils, and WBC counts at Discontinuation (2% to 22%).

There was a greater percentage of patients with shifts in % lymphocytes
to low in patients treated with FP 500 (6%, 118/284) than for FP 250
(3%, 9/305), than placebo (1%, 5/420) at Week 12. The percentage of
patients with shifts in % lymphocytes for FP 500, FP 250, and placebo
were similar at Week 24. The percentage of patients with shifts in %
lymphocytes to low at discontinuation for was higher for FP 500 (16%,
19/117), and SAL 50/FP 250 (22%, 9/41) than for placebo (9%, 16/177)
\[clinstat\\iss\\iss.pdf, page 102\].

There was a greater percentage of patients treated with FP 500 (5%,
13/284) and FP 250 (5%, 15/305) with shifts in % neutrophils to high
than placebo (2%, 9/420) at week 12. The percentage of patients with
shifts in % neutrophils to high was similar at week 24 for FP 500 (4%,
9/241), FP 250 (4%, 11/268), and placebo (3%, 11/357). There was a
greater percentage of patients treated with FP 500 (21%, 24/117) and SAL
50/FP 250 (20%, 8/41) with shifts in % neutrophils to high at
discontinuation than for FP 250 (11%, 11/104), SAL 50/FP 500 (11%,
5/47), and placebo (11%, 619/177) \[clinstat\\iss\\iss.pdf, page 102\].

Shifts in WBC counts to high were similar for FP 500, FP 250, and
placebo groups at Week 12, Week 24, and Discontinuation
\[clinstat\\iss\\iss.pdf, page 102\].

*[Reviewer comment:]{.underline}*

*The shifts in % lymphocytes, % neutrophils, and WBC counts in
FP-treated patients could be systemic corticosteroid effects of inhaled
FP. The high percentage of patients with shifts in % lymphocytes, %
neutrophils, and WBC counts at discontinuation are likely to be in
patients discontinuing from COPD exacerbations who received treatment
with systemic corticosteroids.*

Increases from baseline in ALT were generally similar in each of the
treatment groups at Week 12, Week 25, and Discontinuation. Exceptions
were the SAL 50/FP 250 (12%, 5/42) and SAL 50/FP 500 (9%, 4/47) groups,
which had a higher percentage of patients at Discontinuation with a
shift in ALT to high than the placebo group (4%, 8/179)
\[clinstat\\iss.iss.pdf, page 103\].

Increases from baseline in AST were generally similar in each of the
treatment groups at Week 12, Week 24, and Discontinuation. Exceptions
were the SAL 50/FP 250 group (7%, 3/42) which had an higher percentage
of patients at Discontinuation with a shift in AST to high than the
placebo group (4%, 8/179) \[clinstat\\iss.iss.pdf, page 103\].

There was a greater percentage of patients who had shifts in alkaline
phosphatase to high for FP 250, FP 500, than placebo at Weeks 12, 24,
and Discontinuation. The percentage of patients who had shifts from
baseline to high in alkaline phosphatase at Week 12 for FP 500 was 3%,
(9/287), compared with FP 250 (2%, 7/301) and placebo (1%, 5/414). The
percentage of patients who had shifts from baseline to high in alkaline
phosphatase at Week 24 for FP 500 was 2%, (4/244), compared with and FP
250 (2%, 4/265) and placebo (1%, 5/353). The percentage of patients who
had shifts from baseline to high in alkaline phosphatase at
Discontinuation for FP 500 was 2%, (2/116), compared with and FP 250
(3%, 43/103) and placebo (1%, 2/176) \[clinstat\\iss.iss.pdf, page
103\].

*[Reviewer comment:]{.underline}*

*The higher percentage of patients with shifts of alkaline phosphatase
to high for FP 250 and FP 500 is interesting. It is unclear if these
shifts suggest a liver signal or a bone signal, as isoenzyme data was
not provided. These data may be a chance occurrence, but may also
suggest a systemic effect of inhaled FP.*

In general, there was no meaningful difference in the percentage of
patients who had shifts to high from baseline in glucose at Weeks 12,
24, and Discontinuation for each of the treatment groups. Exceptions
were SAL 50/FP 500 (13%, 16/47) and SAL 50/FP 250 (12%, 5/43), which
were higher than placebo (8%, 14/176) \[clinstat\\iss\\iss.pdf, page
103\]. It should be noted that the sponsor defined an exceptionally
liberal definition for high glucose, \>175 mg/dL in each of these
studies. It is likely that this liberal definition of high glucose would
result in a lower sensitivity of detecting a difference between
treatment groups \[clinstat\\copd\\flta3025.pdf, page 3598;
clinstat\\copd\\sfca3006.pdf, page 6720; clinstat\\copd\\sfca3007.pdf,
page 5787\].

*[Reviewer comment:]{.underline}*

*Hyperglycemia is an effect of systemic corticosteroids. There were
higher percentages of SAL 50/FP 500 and SAL 50/FP 250 patients with
increases in glucose at Discontinuation than placebo patients. There
were no other meaningful differences between treatment groups. This
observation is much less reassuring because of the sponsor's liberal
definition of elevated blood glucose, \>175 mg/dL.*

#### ECG

Twenty-four hour Holter monitoring was conducted at selected centers in
SFCA3006. These data are pertinent to the SAL 50, SAL 50/FP 250, and SAL
50/FP 500 products.

Holter monitoring results did not demonstrate significant differences
among treatment groups \[clinstat\\iss\\iss.pdf, page 127\].

Twelve-lead ECGs were recorded at screening, Week 12, Week 24, and/or
Discontinuation for each of the pivotal studies in this application.
There were no differences between treatment groups in percentage of
patients with clinically significant changes in ECGs from baseline. The
types of clinically significant abnormalities were similar among
treatment groups \[clinstat\\iss\\iss.pdf, pages 128-131\].

Mean QTc intervals, by both Bazette's and Fridericia's formulae, were
similar among treatment groups at Weeks 12, 24, and Discontinuation
\[clinstat\\iss\\iss.pdf, page 136\]. Approximately 95% of patients in
each of the treatment groups had shifts in QTcB from baseline of \<30
msec. The percentage of patients with shifts in QTcB from baseline of
30-50 msec, 50-70 msec, and ≥ 70 msec were similar among treatment
groups \[clinstat\\iss\\iss.pdf, page 137\].

#### HPA axis effects in pivotal studies

HPA axis effects were studied by serum cortisol analyses in FLTA3025.
HPA axis effects were studied at selected sites in SFCA3006 and SFCA3007
by morning plasma cortisol concentrations and short cosyntropin
stimulation testing. These data are reviewed below.

##### Serum cortisol AUC~12~, FLTA3025

In FLTA3025, blood samples for plasma FP and serum cortisol analyses
were obtained at Week 4 at selected sites. Samples were to be collected
immediately prior to dosing and at 0.5, 1, 2, 4, 8, and 12 hours
post-dose \[clinstat\\copd\\flta3025.pdf, page 5298\]. Plasma was
analyzed for FP concentration at each time point using solid phase
extraction in combination with liquid chromatography tandem mass
spectrometry. The sponsor states that this method has been validated to
a limit of quantitation of 10 pg/mL for FP
\[clinstat\\copd\\flta3025.pdf, page 60\].

There were 86 patients who participated in the clinical pharmacology
component of this study, and 28 were treated with placebo, 31 with FP
250, and 27 with FP 500 \[clinstat\\copd\\flta3025.pdf, page 166\]. Key
pharmacodynamic results are displayed in Table 7.8.

Table 7.8. Serum cortisol results, FLTA3025
\[clinstat\\copd\\flta3025.pdf, pages 166, 4855\].

+-----------------+-----------------+-----------------+-----------------+
| **Cortisol      | **Placebo**     | **FP 250**      | **FP 500**      |
| parameter**     |                 |                 |                 |
|                 | **N = 28**      | **N = 31**      | **N = 27**      |
+-----------------+-----------------+-----------------+-----------------+
| Mean Cortisol   | 2673.4          | 2404.2          | 2102.3          |
| AUC~12~,        |                 |                 |                 |
| pmol.hr/mL      | \-              | \- 10.1%        | \- 21.4%        |
|                 |                 |                 |                 |
| ∆ vs. placebo   |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Mean C~min~,    | 123.1           | 116.7           | 85.3            |
| pmol/mL         |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

FP 250 and FP 500 treatment groups had lower mean cortisol AUC~12~ and
mean C~min~ than the placebo group (10% and 21%, respectively, for serum
cortisol AUC). There was a dose-response effect noted with the lowest
cortisol AUC~12~ and C~min~ in FP 500 patients
\[clinstat\\copd\\flta3025.pdf, pages 166, 4855\]. Higher mean cortisol
AUC~12~ levels were noted for current smokers than for former smokers,
consistent with the lower serum FP levels measured in current smoking.
There was no relationship noted between cortisol levels and weight
\[clinstat\\copd\\flta3025.pdf, page 4857\].

*[Reviewer comment:]{.underline}*

*Unfortunately, baseline cortisol levels were not planned for this
study. Change from baseline in AM cortisol level or serum cortisol AUC
would have been more informative than the cross-group comparisons
available from these data derived from Week 4 samples alone. These data
demonstrate measurable systemic effects of inhaled FP. These findings
are not a surprise, given the large dose of FP used. It is important to
note this is clear evidence of systemic activity of FP in this
population, which is corroborated by the single dose crossover study
conducted in normal volunteers (see FLTA1003, later in this section, and
OCPB review). It should also be noted that these effects were noted
early in the course of the study, at Week 4. It would have been
interesting to examine similar data collected later in this study, for
example, Week 24, where one might expect even a higher degree of
suppression of cortisol AUC~12~ levels.*

*Another consideration is the sampling strategy, which was PK in design
and timed around the anticipated C~max~ for inhaled FP. It is possible
that greater differences between treatment groups in HPA axis effects
could have been detected with more frequent sampling to ensure that the
AM cortisol peak had been captured. For example FLTA1003, which used
timed urinary cortisol and should have quantitatively included all
excreted cortisol, showed a reduction to 40 -- 60% of baseline following
a single dose of 1000 mcg FP.*

HPA axis effects were studied at selected sites in SFCA3006 and SFCA3007
with morning plasma cortisol concentrations and short cosyntropin
stimulation testing. Results of cosyntropin stimulation testing are
summarized in Table 7.9. The percentage of patients with pre-stimulation
AM cortisol levels \<4 mcg/dL at Day 1 and Endpoint were similar in each
of the treatment groups. There were no differences between treatment
groups in the percentage of patients with a change in post-stimulation
cortisol \<5.6 mcg/dL \[clinstat\\iss\\iss.pdf, page 122\].

FP 250 (15%), FP 500 (16%), and SAL 50/FP 500 (17%) had the largest
percentage of patients with post-stimulation change in cortisol of \<5.6
mcg/dL at endpoint, compared with placebo (8%), SAL 50 (9%), and SAL
50/FP 250 (9%). However, SAL 50 (12%), FP 250 (10%), SAL 50/FP 250 (9%),
and SAL 50/FP 500 (10%) also had fairly high percentages of patients
with post-stimulation change in cortisol compared with placebo (5%)
\[clinstat\\iss\\iss.pdf, page 122\].

There was an increase in the percentage of patients with
post-stimulation cortisol levels \<14.5 mcg/dL from Day 1 to Endpoint in
all treatment groups. The largest increase in the percentage of patients
with post-stimulation cortisol levels \<14.5 mcg/dL from Day 1 to
Endpoint was in the FP 250 group (6% to 12%). The percentage of patients
with post-stimulation cortisol levels \<14.5 mcg/dL in the other
treatment groups were similar at Day 1 and Endpoint
\[clinstat\\iss\\iss.pdf, page 122\].

*[Reviewer comment:]{.underline}*

*The data for cosyntropin stimulation testing show no evidence of
adrenal suppression, however, cosyntropin stimulation testing is
intended as a means to diagnose adrenal insufficiency and is a fairly
insensitive measure of adrenal suppression and a fairly small number of
patients (15-20%) were tested.*

Table 7.9. Number and percentage of patients with abnormalities in
cosyntropin stimulation testing, all patients with cortisol levels,
pivotal studies in this application \[clinstat\\iss\\iss.pdf, page
122\].

<table>
<colgroup>
<col style="width: 13%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<thead>
<tr class="header">
<th></th>
<th colspan="6">Day 1</th>
<th colspan="6">Endpoint</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td></td>
<td><p>Pbo</p>
<p>N=576</p>
<p>n (%)</p></td>
<td><p>SAL 50</p>
<p>N=341</p>
<p>n (%)</p></td>
<td><p>FP 250</p>
<p>N=399</p>
<p>n (%)</p></td>
<td><p>FP 500</p>
<p>N=391</p>
<p>n (%)</p></td>
<td><p>SAL 50/ FP 250</p>
<p>N=178</p>
<p>n (%)</p></td>
<td><p>SAL 50/ FP 500</p>
<p>N=169</p>
<p>n (%)</p></td>
<td><p>Pbo</p>
<p>N=576</p>
<p>n (%)</p></td>
<td><p>SAL 50</p>
<p>N=341</p>
<p>n (%)</p></td>
<td><p>FP 250</p>
<p>N=399</p>
<p>n (%)</p></td>
<td><p>FP 500</p>
<p>N=391</p>
<p>n (%)</p></td>
<td><p>SAL 50/ FP 250</p>
<p>N=178</p>
<p>n (%)</p></td>
<td><p>SAL 50/ FP 500</p>
<p>N=169</p>
<p>n (%)</p></td>
</tr>
<tr class="even">
<td>Patients with cortisol levels</td>
<td>98 (100)</td>
<td>89 (100)</td>
<td>50 (100)</td>
<td>39 (100)</td>
<td>44 (100)</td>
<td>39 (100)</td>
<td>63 (100)</td>
<td>65 (100)</td>
<td>26 (100)</td>
<td>37 (100)</td>
<td>32 (100)</td>
<td>36 (100)</td>
</tr>
<tr class="odd">
<td><p>Pre-stim AM cortisol</p>
<p>&lt;4 mcg/dL</p></td>
<td>3 (3)</td>
<td>1 (1)</td>
<td>2 (4)</td>
<td>0 (0)</td>
<td>0 (0)</td>
<td>1 (3)</td>
<td>2 (3)</td>
<td>1 (2)</td>
<td>0 (0)</td>
<td>1 (3)</td>
<td>1 (3)</td>
<td>0 (0)</td>
</tr>
<tr class="even">
<td><p>Post-stim change</p>
<p>&lt;5.6 mcg/dL</p></td>
<td>5 (5)</td>
<td>11 (12)</td>
<td>5 (10)</td>
<td>2 (5)</td>
<td>4 (9)</td>
<td>4 (10)</td>
<td>5 (8)</td>
<td>6 (9)</td>
<td>4 (15)</td>
<td>6 (16)</td>
<td>3 (9)</td>
<td>6 (17)</td>
</tr>
<tr class="odd">
<td><p>Post-stim cortisol</p>
<p>&lt;14.5 mcg/dL</p></td>
<td>3 (3)</td>
<td>4 (4)</td>
<td>3 (6)</td>
<td>1 (3)</td>
<td>1 (2)</td>
<td>1 (3)</td>
<td>4 (6)</td>
<td>3 (5)</td>
<td>3 (12)</td>
<td>2 (5)</td>
<td>1 (3)</td>
<td>2 (6)</td>
</tr>
</tbody>
</table>

### Subgroup analyses of safety endpoints in pivotal studies

Subgroup analyses of safety endpoints by gender, age, and race follow.
The safety endpoints analyzed include AEs, deaths and SAEs, withdrawals
due to AEs, laboratory data, HPA axis effects, and ECGs.

#### Subgroup analyses of AEs

The frequency of AEs were higher in females (71% to 83%) than males (61%
to 82%). URTI, headaches, musculoskeletal pain, throat irritation, viral
respiratory infections, and URI were more common in females than in
males, but this difference was present for all treatment groups,
including placebo. There was no consistent association of gender with
AEs for any of the treatment groups \[clinstat\\iss\\iss.pdf, pages 70,
72\].

The overall frequency of AEs was similar in patients \<65 years of age
(67% to 81%) and in those ≥65 years of age (64% to 80%). URTI,
headaches, musculoskeletal pain, throat irritation, and viral
respiratory infections were slightly more common in patients \<65 years
of age than in patients ≥65 years of age, but this difference was
present for all treatment groups, including placebo. There was no
consistent association of age with AEs for any of the treatment groups
\[clinstat\\iss\\iss.pdf, pages 70, 73\].

The overall frequency of AEs differed by race. The overall frequency of
AEs in Caucasian patients ranged from 69% (223/321) to 81% (298/367).
The overall frequency of AEs in Black patients ranged from 47% (8/17) to
72% (13/18). The overall frequency of AEs in patients of Asian or Other
race ranged from 33% (1/3) to 43% (3/7). The difference in frequencies
between the races is likely to be a result of the small sample size of
patients of Black and Asian/Other races. Review of the AEs for patients
of Black and Asian/Other races does not reveal an obvious association
with the type of treatment. The insufficient sample size of patients of
color does not allow for a proper analysis of AEs by race, however.

*[Reviewer comments:]{.underline}*

*The under-representation of non-Caucasian patients in this study is a
serious deficiency of these studies. The sponsor has not adequately
studied the safety of FP in non-Caucasian patients with COPD. Additional
study of the safety of FP in a more racially diverse study population is
strongly encouraged .*

#### Subgroup analyses of deaths and SAEs

All deaths were in placebo-treated patients. There was no association of
gender for the four deaths in the pivotal studies. Two of the four
patients that died were males and two were females. One of the four
patients that died was \<65 years of age (60 years). The other three
were ≥65 years (66, 69, and 72 years). All patients that died in the
pivotal studies were Caucasian \[clinstat\\iss\\iss.pdf, page 83\].

The overall frequency of SAEs was higher in males (4% to 9%) than
females (3% to 6%). Pneumonia, syncope, and fractures were more common
in males, and chest symptoms were more common in females. The frequency
of SAEs by gender were similar among active and placebo treatment groups
\[clinstat\\iss\\iss.pdf, pages 85, 87\]. The overall frequency of SAEs
was slightly lower in patients \<65 years (3% to 7%) than in patients
≥65 years (4% to 8%). Pneumonia appeared to be more common in patients
≤65 years of age who were treated with FP 500 and SAL 50/FP 500.
Fractures appeared to be more common in patients \>65 years of age, but
occurred at similar frequencies in the treatment groups
\[clinstat\\iss\\iss.pdf, page 88\]. The small number of non-Caucasian
patients did not allow for an analysis of SAEs by race
\[clinstat\\iss\\iss.pdf, pages 465-477\].

#### Subgroup analyses of withdrawals due to AEs

The frequency of withdrawal due to AEs was fairly similar in males and
females. Pneumonia, hoarseness/dysphonia, cardiovascular test findings,
CVA, myocardial infarction, palpitations, and tachyarrhythmias were more
common in males than in females, but frequencies were similar among the
treatment groups \[clinstat\\iss\\iss.pdf, page 96\].

The frequency of withdrawal due to AEs was lower in patients \<65 years
of age than in patients ≥65 years of age. Withdrawals due to depressive
disorders, URTI, and viral respiratory infection were more common in
patients \<65 years of age than in patients ≥65 years of age, but were
at similar frequencies in the treatment groups. Withdrawals due to
pneumonias were more common in patients ≥65 years of age who were
treated with FP 500 and SAL 50/FP 500 \[clinstat\\iss\\iss.pdf, page
97\]. The small number of non-Caucasian patients did not allow for an
analysis of withdrawals due to AEs by race \[clinstat\\iss\\iss.pdf,
pages 529-538\].

#### Subgroup analyses of laboratory data

No consistent changes were noted in the percentage of patients with
shifts from baseline in hematology results when analyzed by gender. AST
shifts to high at Discontinuation were noted for more females (0% to
12%) than males (0% to 4%). Shifts from baseline to high glucose levels
were noted in a slightly higher proportion of males (4% to 19%) than
females (0% to 16%). These changes were noted for each of the treatment
groups, including placebo \[clinstat\\iss\\iss.pdf, pages 106-109\].

More males than females had decreased hemoglobin (20 males, 3 females),
decreased hematocrit (8 males, 0 females), and increased WBC (17 males,
0 females). These changes were noted in active as well as in placebo
groups \[clinstat\\iss.\\iss.pdf, pages 114-115\]. Elevated glucose was
noted in more males (42) than females (16), but these changes were noted
in active as well as in placebo groups \[clinstat\\iss\\iss.pdf, pages
114, 116\].

No consistent changes in the percentage of patients with shifts from
baseline in hematology or chemistry results were noted when analyzed by
age \[clinstat\\iss\\iss.pdf, pages 107, 110, 112\]. No consistent
changes in the percentage of patients with abnormal hematology or
chemistry results were noted when examined by age
\[clinstat\\iss\\iss.pdf, pages 114, 117\].

The sponsor did not provide an analysis of laboratory results by race.
The small number of non-Caucasian patients would have prevented a
meaningful analysis of these data.

#### Subgroup analyses of ECGs

Changes in baseline ECG were noted in more males than females. More
clinically significant changes from baseline were noted in patients ≥65
years of age. These changes were noted in active as well as placebo
treatment groups \[clinstat\\iss\\iss.pdf, pages 132-134\].

Median QTcB intervals were slightly increased (5-10 msec) in females
compared with males for each of the treatment groups, active and placebo
for each of the time points \[clinstat\\iss\\iss.pdf, pages 141,
899-912\]. This is an expected gender effect of QTc.

Median QTcB intervals were similar in patients \<65 years of age and in
patients ≥65 years of age for each of the treatment groups, active and
placebo, for each of the time points \[clinstat\\iss\\iss.pdf, pages
141, 941-954\].

The sponsor did not provide an analysis of ECG results by race. The
small number of non-Caucasian patients would have prevented a meaningful
analysis of these data.

#### Subgroup analyses of HPA axis effects

The small number of patients who had cosyntropin stimulation testing
precluded meaningful comparisons between treatment groups for subgroups
\[clinstat\\iss\\iss.pdf, pages 123, 846-862\]. The sponsor provided no
subgroup analysis of cortisol AUC~12~ data for FLTA3025.

### Supportive safety data from other studies

The sponsor provided supportive safety data from other studies. These
data include:

-   AEs and HPA-axis data from clinical pharmacology study FLTA1003

-   Blinded listings of deaths and SAEs from ongoing clinical studies
    SFCB3024, SCO30003

-   Studies of Flovent MDI 500 mcg BID, FLIP63, FLIT78, FLIT97, FLIT98

-   Bone mineral density data from two long-term studies in asthma,
    FLTA3001 and FLTA3017

-   Blinded listings of deaths and SAEs from nine ongoing non-US studies
    used to support regional markets (SCO30001, SCO40002, SMS40026,
    SMS40308, FCO40002, FCO40003, FCO40004, SAM30001)

A review of these supportive safety data from other studies follows
below.

#### AEs and HPA-axis data from clinical pharmacology study FLTA1003

FLTA1003 was a Phase 1 clinical pharmacology and pharmacodynamics study
that was designed to assess the dose-proportionality and HPA-axis
effects of FP when administered by the Diskus
\[hpbio\\bio\\flta1003.pdf, page 13\]. The study was a single-center,
open-label, randomized, single dose, 4-way crossover study. Twenty
patients were to be enrolled in the study. Patients were healthy male
and female subjects, ages 18 to 50 years. Patients were randomized to
one of the following single doses at each of the study's four treatment
periods \[hpbio\\bio\\flta1003.pdf, page 14\]:

-   20 inhalations of 50 mcg strength of FP Diskus, total dose 1000 mcg

-   10 inhalations of 100 mcg strength of FP Diskus, total dose 1000 mcg

-   4 inhalations of 250 mcg strength of FP Diskus, total dose 1000 mcg

-   2 inhalations of 500 mcg strength of FP Diskus, total dose 1000 mcg

There was a minimum wash-out period of 5 days between each 24-hour
treatment period. \[hpbio\\bio\\flta1003.pdf, page 33\].

The dose proportionality of the various dosage strengths will not be
addressed in this section of the review. Dose proportionality is
addressed briefly elsewhere in this review, and in detail in Dr.
Suarez's clinical pharmacology and biopharmaceutics review.

The investigator was responsible for detecting and documenting AEs from
screening until the end of the study \[hpbio\\bio\\flta1003.pdf, page
25\].

Twenty-four hour urine samples were collected before and after each dose
of study medication. Subjects began urine collection the morning after
they were admitted to the study site. The pre-dose collection ended with
the first void of the following day. The post-dose urine collection
began when the second void was collected on that same day and was
continued for 24 hours. Cortisol levels were determined using a
competitive immunoassay on an automated chemiluminescence system. The
range of the assay was 6 nM to 2069 nM.

Twenty-two patients were exposed to study drug, and 20 subjects
completed the study \[hpbio\\bio\\flta1003.pdf, page 25\]. Three of the
22 subjects experienced a total of eleven AEs. Headache was the most
common AE and occurred in two patients. There were no other AEs that
occurred in more than one patient \[hpbio\\bio\\flta1003.pdf, pages 33,
69\]. The frequency of AEs by treatment group is listed below in Table
7.10.

Table 7.10. AEs by treatment group, FLTA1003 \[hpbio\\bio\\flta1003.pdf,
page 33\].

  ----------------- -----------------------------------------------------
  **Treatment**     **AEs reported**

  50 mcg X 20       1 dizziness, 1 chest pain
  inhalations       

  100 mcg X 10      None
  inhalations       

  250 mcg X 4       1 headache, 1 rhinorrhea
  inhalations       

  500 mcg X 2       1 fever, 1 chest congestion, 1 weakness, 1 headache,
  inhalations       1 vertigo, 1 sore throat\*
  ----------------- -----------------------------------------------------

\*AE not noted on CRF \[crf\\flta1003\\54465\]\\p0041713.pdf page 18\]

There were no deaths or SAEs. There was one patient that withdrew due to
an AE. Subject 41713 received treatment with the 500 mcg dosage strength
in the first of the four periods. This patient had a fever, vertigo,
weakness, chest congestion, headache, sore throat. A rash was noted
several days before the first dose \[hpbio\\bio\\flta1003.pdf, page 33,
crf\\flta1003\\54465\]\\p0041713.pdf page 18\]. It is interesting to
note that this subject's 24-hour urinary cortisol excretion decreased
from 11.7 mcg pre-dose to 1.7 mcg post-dose \[hpbio\\bio\\flta1003.pdf,
page 138\].

*[Reviewer comment:]{.underline}*

*AEs provide no evidence of new safety signal.*

Significant decreases in post-treatment urinary cortisol levels were
noted across all treatment groups. These data are displayed in Table
7.11. It is interesting to note that the majority of subjects had
decreases of similar magnitude even after the first of the four
treatment periods \[hpbio\\bio\\flta1003.pdf, pages 138-143\].

Table 7.11. Urinary cortisol excretion data, FLTA1003
\[hpbio\\bio\\flta1003.pdf, page 67\].

+-----------------+-----------------+-----------------+-----------------+
| Treatment group | Mean urinary    | Mean urinary    | Difference,     |
|                 | cortisol        | cortisol        |                 |
|                 | excretion,      | excretion,      | Post-dose minus |
|                 | pre-dose, mcg   | post-dose, mcg  | pre-dose        |
+-----------------+-----------------+-----------------+-----------------+
| 50 mcg X 20     | 18.5            | 9.6             | 8.9             |
| inhalations     |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| 100 mcg X 10    | 22.3            | 13.8            | 8.5             |
| inhalations     |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| 250 mcg X 4     | 19.1            | 12.4            | 6.7             |
| inhalations     |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| 500 mcg X 2     | 18.0            | 7.3             | 10.7            |
| inhalations     |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

*[Reviewer comment:]{.underline}*

*These data show strong evidence of systemic HPA-axis effects in normal
subjects when given 1000 mcg FP by Diskus. Decreases in cortisol
excretion were noted in many subjects as soon as after the first dose of
study treatment. Although COPD patients apparently have less systemic
exposure from inhaled FP than normal subjects, the degree of suppression
noted in this study after a short period of dosing is notable and gives
concern about possible similar effects in the proposed population with
long-term exposure. Cortisol data from FLTA3025 was obtained after 4
weeks of treatment, and cosyntropin stimulation data were obtained after
24 weeks of dosing in SFCA3006 and SFCA3007. Given that cortisol and
cosyntropin data are less sensitive measures of systemic corticosteroid
effects (see "Reviewer Comment" under "Serum Cortisol AUC~12~ FLTA3025",
above) , additional long-term safety data of use of FP in the proposed
population are needed.*

#### Blinded listings of deaths and SAEs from two ongoing controlled clinical studies, SFCB3024 and SCO30003

Blinded listings of deaths and SAEs from two ongoing studies were
provided to supplement the safety portion of this application. These
studies were SFCB3024 and SCO30003. These safety data for each study are
described below.

##### SFCB3024

SFCB3024 is a randomized, double blind, parallel group,
placebo-controlled, non-US, multicenter trial to compared the efficacy
and safety of SAL 50/FP 500 with SAL 50, and FP 500 administered with
the Diskus in patients with COPD. Approximately 1200 patients with COPD
are to be studied for a 52-week treatment period. There had been 1468
patients enrolled as of the cut-off date of 9/30/00
\[clinstat\\iss\\iss.pdf, page 165\].

There were 25 deaths in subjects in SFCB3024 as of the 9/30/00 safety
cut-off date. No death was considered by the investigator to be related
to study treatment. The majority of deaths were cardiovascular in
nature, such as cardiac arrest, cardiac failure, myocardial infarction,
among others. Three deaths were due to exacerbation of COPD
\[clinstat\\iss\\iss.pdf, page 167\].

Most of the SAEs in SFCB3024 are related to exacerbation of COPD. Many
are cardiovascular. There were 3 patients with fractures of the lower
limb and two patients with fractures of the hip. One of the patients
with hip fracture was coded as a drug interaction, overdose and trauma
SAE (Patient #8328) and the other as a neurologic SAE (Patient #08457)
One patient had a candidal infection of the esophagus
\[clinstat\\iss\\iss.pdf, pages 1235-1302\].

*[Reviewer comment:]{.underline}*

*These blinded data do not provide useful information to support the
safety of FP in patients with COPD. The final long-term safety data from
these studies will be essential in determining the safety profile for FP
in this population and to make an appropriate risk-benefit assessment,
particularly given the all-cause and COPD-related mortality already
observed.*

##### SCO30003

SFCB30003 is a randomized, double blind, parallel group,
placebo-controlled, multicenter trial to compared the long-term effects
of SAL 50/FP 500 with SAL 50, and FP 500 administered with the Diskus in
patients with COPD. Approximately 5040 patients with COPD are to be
studied for a 36-month treatment period. There had been 8 patients
enrolled as of the cut-off date of 9/30/00 \[clinstat\\iss\\iss.pdf,
page 165\].

There were no deaths or SAEs reported in this study as of the safety
cut-off date \[clinstat\\iss\\iss.pdf, page 168\].

*[Reviewer comment:]{.underline}*

*There are no data from this study at this time and no safety
information for this application. This study is designed to investigate
all-cause mortality, COPD-related mortality and morbidity, and change in
lung function in COPD patients treated with FP. Results of this study
will be critical to any regulatory decision regarding a COPD indication
for FP.*

#### Study summaries of four non-US studies of Flovent MDI in patients with COPD

Safety data from four completed non-US studies of Flovent MDI were
provided in support of this application. These studies are FLIT78 (also
known as the ISOLDE study), FLIT97, FLIT98, and FLIP63. The sponsor
provided study reports for these studies. This document will review AEs,
deaths, SAEs, and withdrawals due to AEs occurring in these studies. A
brief description of the study design for each of these studies follows.

FLIT78 was a 3-year, non-US, multicenter, double blind,
placebo-controlled, parallel group study of the efficacy and
tolerability of long-term FP 500 mcg BID in COPD. This trial is also
known as the ISOLDE study. The MDI formulation of FP was used with the
Volumatic spacer device. The study included an optional 2-week acute
corticosteroid trial prior to the start of the double-blind inhaled
treatment period. Patients were 40 to 75 years of age. A total of 742
patients were included in the safety analysis, with 372 for FP and 370
for placebo \[clinstat\\iss\\iss.pdf, page 149;
clinstat\\other\\flit78.pdf, page 30\].

FLIT97 was a 6-month, multicenter, international, randomized,
double-blind, parallel group study of the efficacy and safety of inhaled
FP 500 mcg BID with placebo in COPD. The MDI formulation of FP was used
with the Volumatic spacer device, if desired. Patients were 50 to 75
years of age. A total of 281 patients were included in the safety
analysis, with 142 for FP and 139 for placebo \[clinstat\\iss\\iss.pdf,
page 172; clinstat\\other\\flit97.pdf, pages 5, 20, 25, 29\].

FLIT98 was a multicenter, randomized, double-blind, parallel group study
of the efficacy and safety of inhaled FP 1000 mcg BID with placebo over
a 4-week period to determine the number of days needed to recover from
an acute exacerbation of COPD. The MDI formulation of FP was used.
Patients were 50 to 75 years of age. A total of 249 patients were
included in the safety analysis, with 126 for FP and 123 for placebo
\[clinstat\\iss\\iss.pdf, page 172; clinstat\\other\\flit98.pdf, page
5\].

FLIT63 was a single center, randomized, double-blind, parallel group
study of the effects of FP 750 mcg BID compared with placebo on the
inflammatory processes in the lungs of patients with COPD. Patients
received either FP 250 mcg 3 puffs BID via the MDI formulation and using
a Volumatic spacer for an 8-week treatment period. Patients were 40 to
75 years of age. A total of 17 patients were included in the safety
analysis, with 8 for FP and 9 for placebo \[clinstat\\iss\\iss.pdf,
pages 172, 193; clinstat\\other\\flit63.pdf, pages 15, 17\].

##### AEs in FLIT78, FLIT97, FLIT98, and FLIP63

**FLIT78**

The frequency of patients AEs was similar in the FP group (95%, 355/372)
and the placebo group (97%, 359/370). AEs occurring more frequently in
FP than placebo are displayed in Table 7.12. The FP group experienced
higher rates of lower, upper, and viral respiratory infections, throat
irritation, candidiasis mouth/throat, hoarseness/dysphonia, and
pneumonia.

Table 7.12. Most common AEs occurring more frequently in FP than
placebo, FLIT78. Entries represent number (percent) of patients
\[clinstat\\iss\\iss.pdf, page 150\].

+-----------------------+----------------------+-----------------------+
| **Adverse event**     | **Placebo**          | **FP 500 mcg BID**    |
|                       |                      |                       |
|                       | **N = 370**          | **N = 372**           |
|                       |                      |                       |
|                       | **n (%)**            | **n (%)**             |
+=======================+======================+=======================+
| Any AE                | 359 (97)             | 355 (95)              |
+-----------------------+----------------------+-----------------------+
| Lower respiratory     | 132 (36)             | 153 (41)              |
| infections            |                      |                       |
+-----------------------+----------------------+-----------------------+
| Upper respiratory     | 59 (16)              | 75 (20)               |
| tract infections      |                      |                       |
+-----------------------+----------------------+-----------------------+
| Viral respiratory     | 39 (11)              | 60 (16)               |
| tract infections      |                      |                       |
+-----------------------+----------------------+-----------------------+
| Throat irritation     | 27 (7)               | 43 (12)               |
+-----------------------+----------------------+-----------------------+
| Candidiasis           | 24 (6)               | 41 (11)               |
| mouth/throat          |                      |                       |
+-----------------------+----------------------+-----------------------+
| Hoarseness/dysphonia  | 16 (4)               | 35 (9)                |
+-----------------------+----------------------+-----------------------+
| Pneumonia             | 8 (2)                | 22 (6)                |
+-----------------------+----------------------+-----------------------+

The sponsor argues that when the slightly overall higher exposure to
drug was higher in the FP group is taken into account, that the event
rates of all events and infections per subject-year of exposure were
similar between treatment groups. These data are displayed in Table
7.13.

Table 7.13. Infection AEs adjusted for exposure to medication, FLIT78.
Entries represent number (percent) of patients \[clinstat\\iss\\iss.pdf,
page 150\].

+-----------------------+----------------------+-----------------------+
| **Adverse event**     | **Event rate**       | **Event rate**        |
|                       |                      |                       |
|                       | **per subject-year   | **per subject-year of |
|                       | of exposure**        | exposure**            |
+=======================+======================+=======================+
| Any AE                | 1.68                 | 1.51                  |
+-----------------------+----------------------+-----------------------+
| Lower respiratory     | 0.48                 | 0.46                  |
| infections            |                      |                       |
+-----------------------+----------------------+-----------------------+
| Viral respiratory     | 0.06                 | 0.10                  |
| tract infections      |                      |                       |
+-----------------------+----------------------+-----------------------+
| Pneumonia             | 0.01                 | 0.03                  |
+-----------------------+----------------------+-----------------------+

*[Reviewer comment:]{.underline}*

*Even if one accepts the sponsor's argument for adjusting the event
rates for exposure to study medication, the event rate for pneumonia was
three times higher for FP than for placebo, and the rate of viral
respiratory tract infections was 1.7 times higher for FP than for
placebo. These data suggest that respiratory infections, particularly
viral respiratory tract infections and pneumonia may be a safety signal
for FP in the COPD population.*

Selected AEs of low frequency are found in Table 7.14. Most of these AEs
represent effects noted with systemic corticosteroids. The frequencies
of gastrointestinal hemorrhage, diabetes mellitus, hyperglycemia, ocular
pressure disorders, decreased cortisol, abnormal adrenal hormone levels,
Cushing's syndrome/symptoms, hypofunction of adrenal cortex, skin
hemorrhage, acne and folliculitis, muscle atrophy, weakness, and
tiredness were more common in FP than in placebo. The frequencies of
glycosuria and ketonuria, cataracts, fractures, and osteoporosis were
either higher in placebo than FP or occurred at similar frequencies.

Table 7.14. Notable AEs occurring at low frequency during inhaled
treatment, FLIT78. Entries represent number (percent) of patients,
grouped by body system \[clinstat\\other\\flit78.pdf, pages 128,
523-539\].

+-----------------------+----------------------+-----------------------+
| **Adverse event**     | **Placebo**          | **FP 500 mcg BID**    |
|                       |                      |                       |
|                       | **N = 370**          | **N = 372**           |
|                       |                      |                       |
|                       | **n (%)**            | **n (%)**             |
+-----------------------+----------------------+-----------------------+
| Any AE                | 359 (97)             | 355 (95)              |
+-----------------------+----------------------+-----------------------+
|                       |                      |                       |
+-----------------------+----------------------+-----------------------+
| Gastrointestinal      | 3 (\<1)              | 10 (3)                |
| hemorrhage            |                      |                       |
+-----------------------+----------------------+-----------------------+
|                       |                      |                       |
+-----------------------+----------------------+-----------------------+
| Diabetes mellitus     | 3 (\<1)              | 6 (2)                 |
+-----------------------+----------------------+-----------------------+
| Hyperglycemia         | 5 (1)                | 6 (2)                 |
+-----------------------+----------------------+-----------------------+
| Glycosuria and        | 4 (1)                | 2 (\<1)               |
| ketonuria             |                      |                       |
+-----------------------+----------------------+-----------------------+
|                       |                      |                       |
+-----------------------+----------------------+-----------------------+
| Cataracts             | 7 (2)                | 5 (1)                 |
+-----------------------+----------------------+-----------------------+
| Ocular pressure       | 3 (\<1)              | 6 (2)                 |
| disorders             |                      |                       |
+-----------------------+----------------------+-----------------------+
|                       |                      |                       |
+-----------------------+----------------------+-----------------------+
| Fractures             | 17 (5)               | 9 (2)                 |
+-----------------------+----------------------+-----------------------+
| Osteoporosis          | 4 (1)                | 1 (\<1)               |
+-----------------------+----------------------+-----------------------+
|                       |                      |                       |
+-----------------------+----------------------+-----------------------+
| Decreased cortisol    | 2 (\<1)              | 12 (3)                |
+-----------------------+----------------------+-----------------------+
| Abnormal adrenal      | 1 (\<1)              | 3 (\<1)               |
| hormone levels        |                      |                       |
+-----------------------+----------------------+-----------------------+
| Cushing's             | 0 (0)                | 1 (\<1)               |
| syndrome/symptoms     |                      |                       |
+-----------------------+----------------------+-----------------------+
| Hypofunction of       | 0 (0)                | 1 (\<1)               |
| adrenal cortex        |                      |                       |
+-----------------------+----------------------+-----------------------+
|                       |                      |                       |
+-----------------------+----------------------+-----------------------+
| Skin hemorrhage       | 1 (\<1)              | 9 (2)                 |
+-----------------------+----------------------+-----------------------+
| Acne and folliculitis | 0 (0)                | 4 (1)                 |
+-----------------------+----------------------+-----------------------+
|                       |                      |                       |
+-----------------------+----------------------+-----------------------+
| Muscle cramps and     | 10 (3)               | 19 (5)                |
| spasms                |                      |                       |
+-----------------------+----------------------+-----------------------+
| Muscle atrophy,       | 2 (\<1)              | 7 (2)                 |
| weakness, & tiredness |                      |                       |
+-----------------------+----------------------+-----------------------+

*[Reviewer comment:]{.underline}*

*The occurrence of these AEs associated with systemic corticosteroids is
concerning, and suggests that this dose of inhaled FP via the MDI
formulation may result in clinically significant systemic exposure. The
findings in this 3-year study underscore the importance of the recently
started long-term study of FP 500 Diskus in a similar population of COPD
patients, SCO30003.*

**FLIT97**

The overall incidence of AEs was similar for FP (64%) and placebo (68%)
groups. AEs occurring ≥3% and more frequently in FP than in placebo in
FLIT97 are displayed in Table 7.15. URTI, throat irritation, viral
respiratory tract infections, temperature regulation disturbances,
headaches, hoarseness /dysphonia, urinary infections, nausea and
vomiting, and candidiasis mouth/throat occurred more frequently in FP
than in placebo \[clinstat\\iss\\iss.pdf, page 172;
clinstat\\other\\flit97.pdf, pages 176-177\].

Table 7.15. AEs occurring ≥3% and more frequently in FP than placebo,
FLIT97. Entries represent number (percent) of patients
\[clinstat\\other\\flit97.pdf, page 177\].

+-----------------------+----------------------+-----------------------+
| **Adverse event**     | **Placebo**          | **FP 500 mcg BID**    |
|                       |                      |                       |
|                       | **N = 139**          | **N = 142**           |
|                       |                      |                       |
|                       | **n (%)**            | **n (%)**             |
+-----------------------+----------------------+-----------------------+
| Any AE                | 94 (68)              | 91 (64)               |
+-----------------------+----------------------+-----------------------+
| Upper respiratory     | 14 (10)              | 19 (13)               |
| tract infections      |                      |                       |
+-----------------------+----------------------+-----------------------+
| Throat irritation     | 5 (4)                | 8 (6)                 |
+-----------------------+----------------------+-----------------------+
| Viral respiratory     | 4 (3)                | 8 (6)                 |
| tract infections      |                      |                       |
+-----------------------+----------------------+-----------------------+
| Temperature           | 2 (1)                | 8 (6)                 |
| regulation            |                      |                       |
| disturbances          |                      |                       |
+-----------------------+----------------------+-----------------------+
| Headaches             | 6 (4)                | 7 (5)                 |
+-----------------------+----------------------+-----------------------+
| Hoarseness/dysphonia  | 0 (0)                | 5 (4)                 |
+-----------------------+----------------------+-----------------------+
| Urinary infections    | 2 (1)                | 4 (3)                 |
+-----------------------+----------------------+-----------------------+
| Nausea & vomiting     | 1 (\<1)              | 4 (3)                 |
+-----------------------+----------------------+-----------------------+
| Candidiasis           | 0 (0)                | 4 (3)                 |
| mouth/throat          |                      |                       |
+-----------------------+----------------------+-----------------------+

Notable AEs of low frequency are displayed in Table 7.16. There were
small numbers of AEs associated with systemic corticosteroid effects,
and these occurred at similar frequencies in both treatment groups.

Table 7.16. Notable AEs occurring at low frequency during inhaled
treatment, FLIT97. Entries represent number (percent) of patients,
grouped by body system \[clinstat\\other\\flit97.pdf, pages 164-169\].

+-----------------------+----------------------+-----------------------+
| **Adverse event**     | **Placebo**          | **FP 500 mcg BID**    |
|                       |                      |                       |
|                       | **N = 139**          | **N = 142**           |
|                       |                      |                       |
|                       | **n (%)**            | **n (%)**             |
+=======================+======================+=======================+
| Gastrointestinal      | 1 (\<1)              | 0 (0)                 |
| hemorrhage            |                      |                       |
+-----------------------+----------------------+-----------------------+
| Cataracts             | 7 (2)                | 5 (1)                 |
+-----------------------+----------------------+-----------------------+
| Fractures             | 0 (0)                | 2 (1)                 |
+-----------------------+----------------------+-----------------------+
| Decreased cortisol    | 3 (2)                | 2 (1)                 |
+-----------------------+----------------------+-----------------------+

*[Reviewer comment:]{.underline}*

*The AE data from this study are suggestive that that URTI and viral
respiratory tract infections are associated with FP treatment. No signal
suggestive of systemic corticosteroid effect was noted, however, this
study was 6 months in duration and smaller in size than the 3-year
FLIT78 study.*

**FLIT98**

The incidence of AEs were similar in the FP (25%, 32/126) and placebo
(28%, 35/123) groups. Chest symptoms and hoarseness were the only AEs
that occurred ≥3% and more frequently in FP than in placebo
\[clinstat\\other\\flit98.pdf, page 157\]. Two patients in the FP group
(2%, 2/126) had decreased cortisols. No placebo patients had decreases
in cortisol.

Table 7.17. AEs occurring ≥3% and more frequently in FP than placebo,
FLIT98. Entries represent number (percent) of patients
\[clinstat\\other\\flit98.pdf, page 157\].

+-----------------------+----------------------+-----------------------+
| **Adverse event**     | **Placebo**          | **FP 500 mcg BID**    |
|                       |                      |                       |
|                       | **N = 123**          | **N = 126**           |
|                       |                      |                       |
|                       | **n (%)**            | **n (%)**             |
+-----------------------+----------------------+-----------------------+
| Any AE                | 35 (28)              | 32 (25)               |
+-----------------------+----------------------+-----------------------+
| Chest symptoms        | 4 (3)                | 5 (4)                 |
+-----------------------+----------------------+-----------------------+
| Hoarseness/dysphonia  | 0 (0)                | 4 (3)                 |
+-----------------------+----------------------+-----------------------+

*[Reviewer comment:]{.underline}*

*Decreased cortisol was noted in this small study of FP-MDI at 1000 mcg
BID for one month.*

**FLIT63**

The overall incidence of AEs during the treatment period was slightly
higher in the placebo group (67%, 6/9) than in the FP group (50%, 4/8).
The incidence of individual types of AEs was low with little difference
between the treatment groups. Upper respiratory tract infection was the
only AE that occurred in more than one patient, and the incidence was
similar in the FP group (25%, 2/8) and the placebo group (22%, 2/9)
\[clinstat\\other\\flit63.pdf, pages 33, 68\].

*[Reviewer comment:]{.underline}*

*There were few AEs in this study, and they reveal no evidence of a
safety signal for FP.*

##### Deaths in FLIT78, FLIT97, FLIT98, and FLIP63

**FLIT78**

There were 68 deaths that occurred during the inhaled treatment period
in this study, with 36/370 (10%) in the placebo group and 32/372 (9%) in
the FP group. The cause of deaths and their frequencies were fairly
similar in FP and placebo groups \[clinstat\\other\\flit78.pdf, page
121\].

FLIT97

There were two deaths in this study, and both patients who died were
treated with placebo \[clinstat\\other\\flit97.pdf, page 61\].

FLIT98

There was one death in this study. The patient was in the FP treatment
group and had "dyspnea and precordalgia" \[clinstat\\other\\flit98, page
56\].

**FLIT63**

There were no deaths in this study \[clinstat\\other\\flit63, page 33\].

##### SAEs in FLIT78, FLIT97, FLIT98, and FLIP63

**FLIT78**

The frequency of SAEs were similar in the FP group (38%, 141/372) and
the placebo group (40%, 148/370) \[clinstat\\other\\flit78.pdf, page
562\]. SAEs for COPD exacerbation were lower in the FP group (16%,
59/372) than in the placebo group (21%, 78/370). SAEs for pneumonia were
more frequent in the FP group (5%, 18/372) than in the placebo group
(2%, 8/370). Other SAEs occurred at similar frequencies for the two
treatment groups \[clinstat\\other\\flit78.pdf, page 125\].

*[Reviewer comment:]{.underline}*

*The smaller frequency of SAEs for COPD exacerbation is suggestive of
efficacy in the FP group. The higher frequency of SAEs for pneumonia in
the FP group than in the placebo group is congruent with the AE reports
for this study and supported by the AE profiles of several other studies
included in this review.*

**FLIT97**

The frequency of SAEs were similar in the FP group (9%, 13/142) and the
placebo group (9%, 12/139). The types of SAEs noted were similar in the
FP and placebo groups, except for chest pain/discomfort, which occurred
in 4 patients in the FP group and in no patients in the placebo group
\[clinstat\\other\\flit97.pdf, pages 61-62\].

*Reviewer comment:*

*The small numbers of SAEs in this study do not suggest a safety signal
for FP.*

**FLIT98**

The frequency of SAEs were similar in the FP group (2%, 2/126) and the
placebo group (2%, 2/123). One FP patient had a SAE for decreased
cortisol. No narrative was provided for this patient. Another patient in
the FP group suffered a fracture of the right humerus in a fall after
completing treatment. Otherwise, the types of SAEs noted were similar in
the FP and placebo groups \[clinstat\\other\\flit98.pdf, pages 56,
161\].

*Reviewer comment:*

*The SAE for decreased cortisol is suggestive of a significant systemic
corticosteroid effect in some patients treated with FP MDI, 1000 mcg
BID.*

**FLIT63**

There were two SAEs in this study. One placebo patient had an
exacerbation of COPD leading to respiratory failure and one FP patient
developed chest pain with a viral chest infection
\[clinstat\\other\\flit63.pdf, page 34\].

*[Reviewer comment:]{.underline}*

*The small number of SAEs in this study provide little additional safety
information.*

##### Withdrawals due to AEs in FLIT78, FLIT97, FLIT98, and FLIP63

**FLIT78**

An analysis of withdrawals due to AEs was not presented in the study
report for FLIT78 submitted with this application. The frequency of
withdrawals due to AEs was lower in the FP group (29%, 109/376) than in
the placebo group (35%, 131/375) \[clinstat\\other\\flit78.pdf, page
320\].

**FLIT97**

The frequency of withdrawals due to AEs was lower in the FP group (6%,
9/142) than in the placebo group (12%, 16/139)
\[clinstat\\other\\flit97.pdf, page 62\]. The types of AEs resulting in
withdrawal were similar in the two treatment groups
\[clinstat\\other\\flit97.pdf, pages 183-184\].

**FLIT98**

The frequency of withdrawals due to AEs was lower in the FP group (2%,
3/126) than in the placebo group (5%, 6/123)
\[clinstat\\other\\flit98.pdf, page 56\]. The types of AEs resulting in
withdrawal were similar in the two treatment groups
\[clinstat\\other\\flit98.pdf, page 163\].

**FLIT63**

There was one withdrawal due to AEs from this study, a placebo patient
who developed an exacerbation of COPD with respiratory failure
\[clinstat\\other\\flit63.pdf, page 34\].

#### Bone mineral density data from long-term asthma studies FLTA3001 and FLTA3017

The sponsor has conducted two controlled, long-term studies of FP in the
treatment of asthma in which the effects on bone mineral density were
studied. These studies were FLTA3001 and FLTA3017. The sponsor provided
a brief summary of the bone mineral density results for these studies in
support of this application.

In both trials, the sponsor measured bone mineral density in three
areas. These areas were lumbar spine, proximal femur, and total body.
The lumbar spine was the only area that underwent prospective quality
assurance from the osteoporosis central laboratory. Results from the
proximal femur and total body bone mineral density were collected for
observational purposes only, as there was no prospective quality
assurance for these measurements \[clinstat\\iss\\iss.pdf, page 154\].

FLTA3001 was a performed with FP administered with the MDI formulation.
This study was submitted to IND 29,309 and NDA 20-548. Adult patients,
male and premenopausal female, ages 18 to 40 years, with mild to
moderate asthma were studied. There were 160 patients studied for a
104-week treatment period. Patients were randomized to either BID
treatment with placebo, FP 88 mcg, or FP 440 mcg. The sponsor states
that lumbar spine bone mineral density measurements demonstrated no
statistically different treatment effects at 24, 52, 76, and 104 weeks
of double-blind treatment. At week 104, a mean percent increase in bone
mineral density was observed in the placebo group (0.20%) and the FP 88
mcg BID group (0.68%). A mean decrease in bone mineral density was
observed in the FP 440 mcg BID group (-0.28%). The sponsor reported no
significant changes from baseline between treatment groups for the
proximal femur and total body bone mineral density
\[clinstat\\iss\\iss.pdf, page 154\].

Table 7.1.4.7. Bone mineral density results, FLTA3001
\[clinstat\\iss\\iss.pdf, page 154\].

  ----------------------------------- -----------------------------------
  **Treatment group**                 **Change from baseline at Week 104,
                                      %**

  Placebo                             0.20

  FP MDI 88 mcg BID                   0.68

  FP MDI 440 mcg BID                  -0.28
  ----------------------------------- -----------------------------------

FLTA3017 was a performed with FP administered with the Rotadisk
formulation. This study was submitted to IND 40,142 and NDA 20-549.
Adult patients, male and premenopausal female, ages 18 to 40 years, with
mild persistent asthma were studied. There were 160 patients studied for
a 104-week treatment period. Patients were randomized to either BID
treatment with placebo or FP 500 mcg. The sponsor states that lumbar
spine bone mineral density measurements demonstrated no statistically
different treatment effects at 24, 52, 76, and 104 weeks of double-blind
treatment. At week 104, a mean percent decreases in bone mineral density
were observed in both the placebo group (-0.54%) and the FP 500 mcg BID
group (-0.43%). The sponsor reported no significant changes from
baseline between treatment groups for the proximal femur and total body
bone mineral density \[clinstat\\iss\\iss.pdf, page 154\].

Table 7.1.4.2 Bone mineral density results, FLTA3017
\[clinstat\\iss\\iss.pdf, page 154\].

  ----------------------------------- -----------------------------------
  **Treatment group**                 **Change from baseline at Week 104,
                                      %**

  Placebo                             -0.54

  FP Rotadisk 500 mcg BID             -0.43
  ----------------------------------- -----------------------------------

*[Reviewer comment:]{.underline}*

*The lumbar spine was only body site that underwent prospective quality
assurance in both of these studies. It appears that from The Lung Health
Study^1^, the femoral neck is a more sensitive area to screen for
decreased bone density. A decrease in bone mineral density in patients
using 1200 mcg of triamcinolone per day was not noted until after three
years of treatment. No changes in bone mineral density were noted at one
or two years of treatment. Both FLTA3001 and FLTA3017 studied younger
patients who had asthma. The Lung Health Study included COPD patients
that represented an older population than was studied in FLTA3001 and
FLTA3017. Patients studied in The Lung Health Study also included a high
percentage of smokers, as well as postmenopausal women. The population
studied in the Lung Health Study is more similar to the proposed
population for this application, and represents a population that would
be at higher risk for decreases in bone mineral density than the
population studied in FLTA3001 and FLTA3017.*

*There is some suggestion of a signal for the FP MDI 440 mcg BID group
in FLTA3001 for this site. The MDI formulation is more systemically
bioavailable than the dry powder formulation used in the Rotadisk and
Diskus, however. One cannot draw useful conclusions in FLTA3001 and
FLTA3017 from the lack of observed effect in the other body areas, as
these areas did not have prospective quality assurance. At best, studies
FLTA3001 and FLTA3017 show no evidence of effect on bone mineral density
with these doses of FP after two years of treatment. However, lack of
effect in these studies does not rule out effects in a more sensitive
site or population, such as that proposed in this application. At worst,
FLTA3001 suggests a decrease in bone mineral density at the end of 2
years of treatment. These studies provide little support for the safety
of FP for the proposed indication and population.*

*The sponsor is planning to prospectively assess bone mineral density in
COPD patients in SCO30003 \[clinstat\\iss\\iss.pdf, page 149;
clinstat\\copd\\sco30003.pdf, page 1\]. Patients are to be treated with
FP 500 mcg BID, SAL 50/FP 500 BID, SAL 50 BID, or placebo BID. The study
will use the Diskus formulations of study treatment. Bone density will
be evaluated over three years in a subpopulation of 600 patients. The
study will also assess bone fractures and ocular events in the entire
study population of 5000 patients \[clinstat\\iss\\iss.pdf, page 149\].
The long-term safety data that will be provided in this study will be
critical in assessing the long-term risk/benefit analysis for this
product in the proposed population.*

#### Blinded listings of deaths and SAEs from ongoing non-US studies used to support regional markets

The sponsor provided blinded information on deaths and SAEs from nine
ongoing local studies used to support regional markets. There were 3228
patients enrolled in these studies as of 9/30/00, which was the safety
cut-off date. These studies were SCO30001, SCO40002, SMS40026, SMS40130,
SMS40308, SAM30001, FCO40003, FCO30002, and FCO40004
\[clinstat\\iss\\iss.pdf, page 177\].

A total of 11 deaths were reported in the local studies as of the safety
cut-off date of 9/30/00. Cardiovascular events were the cause of 8 of
these 11 deaths. No deaths were considered by the investigator to be
related to study drug treatment \[clinstat\\iss\\iss.pdf, pages 177-178,
1303-1306\].

A total of 123 SAEs occurred in 87 patients in the local studies as of
the safety cut-off date. The majority of the SAEs were related to the
lower respiratory tract. There were 72 SAEs that involved the lower
respiratory tract. Most of these were exacerbation of COPD and
pneumonia. Many were cardiovascular and involved cardiac failure,
cardiac arrest, and cerebrovascular accident, among others
\[clinstat\\iss\\iss.pdf, pages 179, 1307-1326\]. One patient
(B0087880A) had exacerbation of diabetes mellitus and urosepsis
\[clinstat\\iss\\iss.pdf, page 1307\].

*[Reviewer comment:]{.underline}*

*These data do not reveal any new safety signal for FP.*

### Spontaneous postmarketing reports

Spontaneous postmarketing reports are reviewed in Dr. Gilbert-McClain's
medical officer review of the Advair product for the COPD indication,
NDA 21-077, S003.

### Safety update

The sponsor's safety update is reviewed in Dr. Gilbert-McClain's medical
officer review of the Advair product for the COPD indication, NDA
21-077, S003.

### References

1.  The Lung Health Study Research Group. Effect of inhaled
    triamcinolone on the decline in pulmonary function in chronic
    obstructive pulmonary disease. New Engl J Med
    2000;343(26):1902-1909.

# Dosing, regimen, and administration issues

The pivotal studies were conducted using FP Diskus 500 mcg, 1 puff BID
for the 24-week double-blind study periods (FLTA3025 and SFCA3006) and
FP Diskus 250 mcg, 1 puff BID for the 24-week (FLTA3025 and SFCA3007).

The FP Diskus 500 mcg is not an approved product, and the sponsor is not
seeking approval of this product for this indication in this
application. The sponsor's proposed starting dosage for COPD is 1
inhalation (250 mcg) twice daily. The proposed labeling allows for
increasing the dose to 2 inhalations (500 mcg) twice daily to provide
additional control for patients who do not respond adequately to the
starting dose \[labeling\\clean.pdf, page 23\].

The sponsor has argued dose proportionality of the approved FP 250 mcg
and proposed FP 500 mcg Diskus products in another study included in
this submission, FLTA1003. However the FP 250 Diskus appears to be more
than dose proportional to the FP 500 Diskus device in the multiple dose,
4-week study FLTA3025.

The primary efficacy endpoint data in the pivotal studies showed a
statistically significant treatment effect for the FP 500 mcg BID when
administered with the FP 500 Diskus. However, the effect was modest and
was offset by the largely negative secondary efficacy endpoint data and
by the lack of effect on health-related quality of life. Furthermore,
most of the secondary efficacy variables and the health-related quality
of life instrument did not support the efficacy of FP 500 mcg BID when
administered with the FP 500 Diskus. The sponsor has not studied the
efficacy or safety of FP 500 mcg BID when administered as 2 inhalations
BID of the FP 250 Diskus. The pivotal studies do not appear to support
the efficacy of the FP 250 BID when administered with the to-be-marketed
FP 250 mcg Diskus product, as a statistically significant difference
from placebo was not noted in replicate studies. The fact that the FP
250 mcg Diskus appears to be more than dose proportional to the FP 500
mcg Diskus raises additional concerns about the safety of the proposed
labeled dose.

Examination of safety data for the pivotal studies reveals a dose
response effect for FP 500 mcg BID and FP 250 mcg BID for upper
respiratory tract infections (URTI), headaches, viral respiratory
infections, candidiasis of the mouth or throat, nasal
congestion/blockage, and muscle pain.

# Use in special populations

## Efficacy in special populations

The under-representation of non-Caucasian patients in this study is a
serious deficiency of these studies. The sponsor has not adequately
studied the efficacy or safety of FP in non-Caucasian patients with
COPD. Additional study of the safety of FP in a more racially diverse
study population is indicated. Efficacy and safety data from future
studies should be examined to determine if the increases in COPD
exacerbations in women and patients ≥65 years represent true safety
signals.

### Analysis of efficacy by gender

The sponsor provided subgroup analyses of efficacy by gender, race, and
age. Males had greater absolute mean changes from baseline in FEV~1~ at
endpoint than women for all active treatment groups. Mean percent change
from baseline in FEV~1~ at endpoint was similar for men and women,
however, indicating the larger absolute mean change in men was due to
larger lung volumes. The mean change from baseline in CBSQ GAS was
similar in men and women for treatment groups. Women had slightly
greater TDI scores at endpoint than men. Women in FP 500 and FP 250
groups had slightly more COPD exacerbations than did men, but this
observation was also present in the placebo group. Women in the FP 500
and FP 250 groups had more slightly more moderate or severe COPD
exacerbations than men, when compared with data for the placebo group.

### Analysis of efficacy by age

No consistent difference in mean change from baseline in FEV~1~ was
noted for all treatment groups when data for patients \<65 years and ≥65
years were compared. Changes in the CBSQ GAS were similar among
treatments for patients \<65 years and ≥65 years. Changes in TDI scores
were similar among treatments for patients \<65 years and ≥65 years.
Incidences of COPD exacerbations in the FP 500 and FP 250 groups
relative to placebo were higher for patients ≥65 years than those \<65
years. Incidences of COPD exacerbations in the FP 500 group relative to
placebo were higher for patients ≥65 years than those \<65 years.

### Analysis of efficacy by race

As noted in each of the individual study reviews in this document, the
vast majority of patients in this study were of Caucasian race. There
were few patients of Black or Asian race. Non-Caucasian races
represented 6% or less of each of the treatment groups. The small number
of Non-Caucasian patients makes it difficult to draw firm conclusions.
Mean percent change from baseline in FEV~1~ at endpoint by race appeared
to be greatest in patients of Other race, followed by patients of Black
race, with the smallest in Caucasian patients. Changes in the CBSQ GAS
appeared to be similar among racial subgroups. COPD exacerbations and
moderate or severe COPD exacerbations appeared to be most frequent in
patients of Black race, followed by Caucasian patients, and lowest in
patients of Other race.

## Safety in special populations

No patients were studied in the pediatric age group, and therefore there
is no analysis of this subgroup. The sponsor has requested a waiver of
pediatric studies in children 0-16 years of age. The sponsor's
justification for this request for waiver is that COPD, as defined by
the American Thoracic Society, does not occur in this age group
\[pediatricwaiverrequest.pdf, page 1\].

There were no pregnancies reported in the conduct of the pivotal
studies, and therefore there is no analysis of this subgroup.

Safety in other special populations is discussed below.

### Analysis of safety by gender

The frequency of AEs was higher in females (71% to 83%) than males (61%
to 82%). URTI, headaches, musculoskeletal pain, throat irritation, viral
respiratory infections, and URI were more common in females than in
males, but this difference was present for all treatment groups,
including placebo. There was no consistent association of gender with
AEs for any of the treatment groups. There was no association of gender
for the four deaths in the pivotal studies. Two of the four patients
that died were males and two were females.

The overall frequency of SAEs was higher in males (4% to 9%) than
females (3% to 6%). Pneumonia, syncope, and fractures were more common
in males, and chest symptoms were more common in females. The frequency
of SAEs by gender was similar among active and placebo treatment groups.
The frequency of withdrawal due to AEs was fairly similar in males and
females. Pneumonia, hoarseness/dysphonia, cardiovascular test findings,
CVA, myocardial infarction, palpitations, and tachyarrhythmias were more
common in males than in females, but frequencies were similar among the
treatment groups.

No consistent changes were noted in the percentage of patients with
shifts from baseline in hematology results when analyzed by gender. AST
shifts to high at Discontinuation were noted for more females (0% to
12%) than males (0% to 4%). Shifts from baseline to high glucose levels
were noted in a slightly higher proportion of males (4% to 19%) than
females (0% to 16%). These changes were noted for each of the treatment
groups, including placebo.

More males than females had decreased hemoglobin (20 males, 3 females),
decreased hematocrit (8 males, 0 females), and increased WBC (17 males,
0 females). These changes were noted in active as well as in placebo
groups. Elevated glucose was noted in more males (42) than females (16),
but these changes were noted in active as well as in placebo groups.
Changes in baseline ECG were noted in more males than females.

Median QTcB intervals were slightly increased (5-10 msec) in females
compared with males for each of the treatment groups, active and placebo
for each of the time points. This is an expected gender effect of QTc.

### Analysis of safety by age

The overall frequency of AEs was similar in patients \<65 years of age
(67% to 81%) and in those ≥65 years of age (64% to 80%). URTI,
headaches, musculoskeletal pain, throat irritation, and viral
respiratory infections were slightly more common in patients \<65 years
of age than in patients ≥65 years of age, but this difference was
present for all treatment groups, including placebo. There was no
consistent association of age with AEs for any of the treatment groups.
One of the four patients that died was \<65 years of age (60 years). The
other three were ≥65 years (66, 69, and 72 years).

The overall frequency of SAEs was slightly lower in patients \<65 years
(3% to 7%) than in patients ≥65 years (4% to 8%). Pneumonia appeared to
be more common in patients ≤65 years of age who were treated with FP 500
and SAL 50/FP 500. Fractures appeared to be more common in patients \>65
years of age, but occurred at similar frequencies in the treatment
groups. The frequency of withdrawal due to AEs was lower in patients
\<65 years of age than in patients ≥65 years of age. Withdrawals due to
depressive disorders, URTI, and viral respiratory infection were more
common in patients \<65 years of age than in patients ≥65 years of age,
but were at similar frequencies in the treatment groups. Withdrawals due
to pneumonias were more common in patients ≥65 years of age who were
treated with FP 500 and SAL 50/FP 500.

No consistent changes in the percentage of patients with shifts from
baseline in hematology or chemistry results were noted when analyzed by
age. No consistent changes in the percentage of patients with abnormal
hematology or chemistry results were noted when examined by age. More
clinically significant changes from baseline were noted in patients ≥65
years of age. These changes were noted in active as well as placebo
treatment groups. Median QTcB intervals were similar in patients \<65
years of age and in patients ≥65 years of age for each of the treatment
groups, active and placebo, for each of the time points.

### Analysis of safety by race

The overall frequency of AEs differed by race. The overall frequency of
AEs in Caucasian patients ranged from 69% (223/321) to 81% (298/367).
The overall frequency of AEs in Black patients ranged from 47% (8/17) to
72% (13/18). The overall frequency of AEs in patients of Asian or Other
race ranged from 33% (1/3) to 43% (3/7). The difference in frequencies
between the races is likely to be a result of the small sample size of
patients of Black and Asian/Other races. Review of the AEs for patients
of Black and Asian/Other races does not reveal an obvious association
with the type of treatment. The insufficient sample size of patients of
color does not allow for a proper analysis of AEs by race, however. All
patients that died in the pivotal studies were of Caucasian race. The
small number of non-Caucasian patients did not allow for an analysis of
SAEs, withdrawals due to AEs, laboratory results, or ECG results by
race.

# Conclusions and recommendations

This is an NDA supplement for a chronic obstructive pulmonary disease
(COPD) indication for Flovent® Diskus®. The sponsor is GlaxoSmithKline.
The proposed indication is the long-term maintenance treatment of COPD.
The proposed starting dose for adults is one inhalation (250 mcg) twice
daily. The proposed labeling allows for increasing the dose to 2
inhalations (500 mcg) twice daily to provide additional control for
patients who do not respond adequately to the starting dose. The
clinical program was also designed to pursue COPD indications for
Serevent Diskus (salmeterol xinafoate 50 mcg) and Advair Diskus
(salmeterol xinafoate 50 mcg/fluticasone propionate 250 mcg and
salmeterol xinafoate 50 mcg/fluticasone propionate 500 mcg). Submissions
similar to the Flovent Diskus NDA supplement have been simultaneously
submitted to the Serevent Diskus NDA (NDA 20-692) and to the Advair
Diskus NDA (NDA 21-077).

These studies do not appear to sufficiently support the efficacy of FP
500 or FP 250 in the treatment of COPD. The main issues included the
patient population studied, inconsistent findings in the three pivotal
studies with the primary endpoint, the absence of strong support from
the secondary endpoints, and the failure of the studies to fully support
the clinical relevance of the primary endpoint, particularly with regard
to the quality of life (QOL) instrument and COPD exacerbation.

With regard to the patient population, the sponsor has not adequately
studied the efficacy of FP in non-Caucasian patients with COPD.
Additional study of the efficacy of FP in a more racially diverse study
population is indicated. There are serious questions about whether the
patient population studied, of which 51% to 59% were highly reversible,
is representative of the US COPD population as a whole, for which a
broad indication is sought. Although statistical significance was shown
for FP 500, the effect size was relatively modest, particularly for
FLTA3025, where 24 weeks of treatment resulted in a net improvement in
FEV~1~ of only 50 mL. It should be noted that this result was also
heavily driven by the "reversible" subgroup and by subjects who had
stopped smoking. These studies do not appear to support the efficacy of
FP 250 in the population studied, as a statistically significant
difference from placebo was not noted in replicate studies. In general,
most of the secondary efficacy variables did not support the efficacy of
FP 500 or FP 250. Secondary efficacy variables that would be expected to
be correlated to the primary endpoint, such as PEFR, showed modest
treatment effects and therefore do not add substantially to the argument
in favor of efficacy for this product.

The quality of life (QOL) instrument, the CRDQ, does not support the
efficacy of FP 500 or FP 250. This is particularly concerning because
all three of the pivotal studies had evaluation of QOL as one of their
primary objectives. This was included because relatively short-term (6
months) changes in FEV~1~ have uncertain clinical significance and do
not have the same correlation with mortality that long-term (3 year)
changes would have. The small effect size in FEV~1~ combined with the
observation that the patients experienced no detectable benefit vs.
placebo in a well-validated QOL instrument argues strongly against a
conclusion of efficacy for FP for the COPD indication.

The sponsor does not appear to have established the safety of FP in the
proposed population. The sponsor has not adequately studied the safety
of FP in non-Caucasian patients with COPD. Additional study of the
safety of FP in a more racially diverse study population is indicated.
The pivotal studies were likely to be of insufficient duration to detect
differences between treatment groups for uncommon events such as
fractures, cataracts, ocular pressure disorders, and disorders of
glucose metabolism. The pivotal studies were not designed to
specifically look for cataracts or systemic bone effects. Safety data
from supportive studies raise concerns about a higher incidence of
respiratory infections, pneumonia, HPA axis effects, among others, in
FP-treated patients, and do not adequately address bone effects in the
proposed population.

The sponsor has recently started a 3-year study of FP 500 mcg BID in
COPD patients (SCO30003). Bone density is to be evaluated over three
years in a subpopulation of 600 patients. This study will also assess
bone fractures and ocular events in the entire study population of 5000
patients. The long-term safety data that will be provided in this study
will be critical in assessing the long-term risk/benefit analysis for
this product in the proposed population.

The sponsor does not appear to have sufficiently established that the
proposed dose of FP is effective or safe in the treatment of COPD.

# APPENDIX: CLINICAL STUDIES

## FLTA3025: A randomized, double-blind, parallel-group, comparative trial of inhaled fluticasone propionate 250 mcg BID, 500 mcg BID, and placebo BID via the Diskus in subjects with chronic obstructive pulmonary disease (COPD)

> Study initiated: 8/8/98
>
> Study completed: 3/8/00
>
> Study report dated: 2/5/01

\[clinstat\\copd\\flta3025.pdf, page 1\]

### Summary and reviewer\'s conclusion of study results

This was a randomized, double-blind, placebo-controlled, parallel group,
multicenter, 24-week trial designed to evaluate the efficacy and safety
of fluticasone propionate (FP) Diskus 250 mcg and 500 mcg in patients
with chronic obstructive pulmonary disease (COPD).

The patient population studied was characterized by a significant amount
of reversibility with bronchodilator. The mean change in FEV~1~ with
bronchodilator for the study population was 22.9%. Of all study
patients, 59% were considered to be reversible (≥12% and ≥200 mL
increase in FEV~1~ with bronchodilator). The mean change in FEV~1~ with
bronchodilator for the reversible group was 32.4%. The population that
was considered to be non-reversible (41% of COPD patients recruited) had
a mean increase of 9.2% in FEV~1~ with bronchodilator. There are serious
concerns as to whether this patient population is representative of the
COPD population as a whole^1-4^, as broadly stated in the labeling for
the proposed indication. This is a critical deficiency of this study.
Under-representation of non-Caucasian patients, who make up a
substantial proportion of the COPD population^1-3^ was another important
deficiency of this study.

The primary efficacy endpoint was the mean change in FEV~1~ from
Baseline to study end point. A small mean change from baseline in FEV~1~
(61 mL) was noted for the FP 500 group (p = 0.010 vs. placebo), compared
to 38 mL (p = 0.140 vs. placebo) for the FP 250 group, and 11 mL for the
placebo group. Values for the mean change in FEV~1~ from Baseline for
the FP 500 group at Weeks 6, 12, and 24 were also small and ranged from
56 mL to 67 mL more than the placebo group. Values for the mean change
from baseline for the FP 250 group at Weeks 6, 12, and 24 ranged from 23
to 37 mL more than the placebo group. Subgroup analysis revealed that
the small amount of efficacy observed was carried entirely by the
population of patients who were former smokers.

Among secondary efficacy endpoints, the Global Assessment Score (GAS) of
the Chronic Bronchitis Symptom Questionnaire (CBSQ) for FP 500, was
numerically greater than placebo, but the difference between FP 500 and
placebo was less than the minimally clinically important change. This
instrument was also administered in such a fashion that the interviewer
might have influenced patient responses. The sponsor reported
improvements in Transitional Dyspnea Indices (TDIs) for FP 500 and FP
250, but these were not significantly different from those noted for the
placebo group. Furthermore, individual components of this instrument
were likely to be highly correlated.

A lower frequency of COPD exacerbations was seen with FP 500 and FP 250,
with dose ordering noted, but the standard definition of COPD
exacerbation^5-7^ was not used and the instrument that was selected
likely favored the finding of efficacy for FP in a COPD population with
a high degree of reversibility.

Small but clinically insignificant changes in other secondary endpoints
were noted, including PEFR, supplemental Ventolin use, and nighttime
awakenings requiring Ventolin use. It should also be noted that PEFR and
use of bronchodilator would be expected to be more likely to show a
treatment effect in a population of COPD patients with a high degree of
reversibility. The overall score of the Chronic Respiratory Disease
Questionnaire (CRDQ), a COPD-related quality of life instrument, did not
show a clinically significant difference between treatment groups.

The sponsor performed a subgroup analysis of efficacy for non-reversible
patients. On the primary endpoint, this subgroup analysis demonstrated
only a small change in FEV~1~ from baseline at study endpoint for FP 500
compared with FP 250 and placebo, indicating that efficacy for this
study was "carried" by the reversible patients. Secondary endpoints in
general corroborated the findings of the primary endpoint, in that each
demonstrated either no change or small, clinically insignificant changes
for FP 500 and FP 250 in the non-reversible population. In conclusion,
subgroup analysis demonstrated little efficacy in the non-reversible
population and indicates that efficacy was carried by those patients in
the reversible population, who constituted the majority of COPD subjects
recruited for this study (59%).

A steady state PK/PD assessment was performed at 4 weeks into this
24-week study. Mean FP AUC~last~ and FP C~max~ were 74% and 58% higher
for FP 500 than FP 250, respectively, indicating a dose-related increase
in systemic exposure that was not dose-proportional. Mean FP AUC~last~
for current smokers was lower than for former smokers. A linear
relationship between weight and FP AUC~last~ was noted for FP 500, but
not FP 250. The study was conducted using 500 mcg Flovent Diskus. The
Flovent 250 mcg Diskus and the Flovent 500 mcg Diskus were not found to
be dose-proportional. The lack of dose proportionality is discussed in
depth in Dr. Suarez's biopharmaceutics review.

With regard to PD (HPA-axis assessment), FP treatment groups had lower
mean cortisol AUC~12~ and mean C~min~ than the placebo group, with a
dose response effect noted. Mean cortisol AUC~12~ was 21% lower than
placebo for FP 500 and 10% lower than placebo for FP 250, indicating
dose-related systemic absorption and systemic activity from Flovent
Diskus that is both acute (see PK study FLTA1003) and chronic. The mean
cortisol AUC~12~ was higher in current smokers than in former smokers.
There was no relationship noted between cortisol levels and weight. It
should be noted that samples were taken at Week 4, early in the study.
These effects might be more pronounced if samples were drawn later in
the study.

Duration of exposure was inadequate to fully assess safety, since the
short efficacy endpoints in this study fail to address the safety
consequences of long-term (\> 6 months) use of high-dose, high-potency
inhaled corticosteroids, particularly with regard to bone,
dermatological, and ocular adverse events, as well as the potential for
HPA axis recovery. A dose-response effect was noted for AEs. AEs
occurred in 80% of FP 500-treated patients, 76% of FP 250-treated
patients, and in 74% of placebo-treated patients. AEs occurring more
frequently with FP 500 and FP 250 than with placebo included upper
respiratory tract infection, headaches, candidiasis of the mouth or
throat, throat irritation, musculoskeletal pain, viral respiratory
infection, upper respiratory inflammation, nasal congestion/blockage,
hoarseness/dysphonia, and sinusitis. A dose response effect for FP 500
and FP 250 was noted for candidiasis of the mouth or throat (placebo
\<1%, FP 250 6%, FP 500 13%), viral respiratory infections (placebo 51%,
FP 250 6%, FP 500 9%), and upper respiratory inflammation (placebo 5%,
FP 250 6%, FP 500 7%). There were no deaths in this study and the
frequency of serious adverse events was similar in each treatment group
(placebo 6%, FP 250 7%, FP 500 7%). Vital signs and ECGs showed no
clinically significant differences between treatment groups.

In summary, small changes in FEV~1~ were noted for the FP groups in this
study, but whether the study population reflects the overall population
of US COPD patients for which this drug is proposed is highly
questionable^1-4^. There are also questions about the clinical relevance
of isolated, short term changes in FEV~1~ to overall benefit in COPD^8^.
For this reason, the failure of secondary efficacy variables to support
the efficacy of FP 250 or FP 500 are of serious concern. As noted above,
efficacy was carried by the subgroup of "reversible" patients,
particularly those who had ceased smoking. The latter observation
confounds the interpretation of ICS as providing an "anti-inflammatory"
benefit since cessation of smoking itself is associated with a reduction
in ongoing airway inflammation^8^. Safety and PK/PD data raise concerns
because of the evidence of dose-related systemic effects on the HPA
axis. The study was of insufficient duration for known systemic
corticosteroid effects such as osteoporosis, cataracts, hypertension,
diabetes, or skin changes such as easy bruisability to become apparent.
It should be noted that the study was not designed to specifically
assess these AEs, and patients with prior pathological fracture,
osteoporosis, significant hypertension or diabetes, cataracts, or
glaucoma were specifically excluded. This study does not appear to
support the efficacy of FP 250 or FP 500 in the treatment of COPD, and
inadequately addresses the safety of these products in this population.

### Study design

This was a randomized, double-blind, placebo-controlled, parallel group,
multicenter trial of 24 weeks duration. Approximately 600 patients were
to be randomized at a minimum of 50 study centers. A total of 640
patients received treatment at 55 US study sites
\[clinstat\\copd\\flta3025.pdf, page 29\]

### Objectives

This study had four objectives \[clinstat\\copd\\flta3025.pdf, page
5273\]. They were:

1.  To evaluate the efficacy of FP 250 mcg and 500 mcg BID compared to
    placebo when administered by the Diskus over a 24-week treatment
    period in the treatment of COPD patients

2.  To evaluate the safety of FP 250 mcg and 500 mcg BID compared to
    placebo when administered via the Diskus over a 24-week treatment
    period in the treatment of COPD patients

3.  To compare quality of life (QOL) in COPD patients receiving FP 250
    mcg BID, FP 500 mcg BID, or placebo over a 24-week treatment period

4.  To describe the steady-state FP pharmacokinetics and serum cortisol
    levels in COPD patients following 250 mcg and 500 mcg BID doses

### Inclusion criteria

Inclusion criteria for this study are listed below. These reflect
protocol amendments. \[clinstat\\copd\\flta3025.pdf, pages 5275-5278,
5356, 5399\]:

1.  Age ≥40 years

2.  Male or female gender

-   A female was eligible to enter and participate if she was of
    non-childbearing potential or was of child-bearing potential with a
    negative serum pregnancy test at screening and an acceptable method
    of contraception

3.  Established history of COPD in accordance with the American Thoracic
    Society (ATS) definition^1^:

-   Abnormal tests of expiratory flow that do not change markedly over
    periods of several months

-   Airflow obstruction may be structural or functional

-   Bronchial hyperreactivity may be present as measured by improvement
    after inhalation of a beta-adrenergic agent or worsening after
    inhalation of methacholine or histamine

-   Emphysema and chronic bronchitis are incorporated into COPD, and any
    individual may have one or both of these conditions

4.  A history of cough productive of sputum on most days for at least 3
    months of the year, for at least 2 years, that is not attributed to
    another disease process. Patients must have a score of ≥8 on the
    Chronic Bronchitis Symptom Questionnaire (CBSQ) at Treatment Day 1

5.  Current or prior history of at least 20 pack-years of cigarette
    smoking. If the patient is an ex-smoker, smoking must have been
    discontinued for at least 6 months prior to screening. Current
    smokers were counseled regarding the hazards of continuing to smoke
    and the benefits of discontinuation. Patient who decided to stop
    smoking at the Screening Visit were not eligible for participation
    in the study. Patients making a conscious decision to stop smoking
    at anytime during the study and who refrain from smoking for \>4
    weeks were to be discontinued from the study. Patients who start
    smoking during the study and smoke for at least 7 consecutive days
    were to be discontinued from the study.

6.  Severity

-   Baseline FEV1\<65% or predicted but \>0.70 L, or FEV1 ≤0.70 L and
    \>40% of the predicted normal value (Crapo), and

-   FEV~1~/FVC ratio of ≤70% at screening

7.  A score if ≥2 in the Modified Medical Research Council Dyspnea Scale
    at screening:

Modified Medical Research Council Dyspnea Scale

  ----------- ---------------------------------------------------------------
  **Grade**   **Description**

  0           Not troubled with breathlessness except with strenuous exercise

  1           Troubled by shortness of breath when hurrying on the level or
              walking up a slight hill

  2           Walks slower than people of the same age on the level because
              of breathlessness or has to stop for breath when walking at own
              pace on the level

  3           Stops to breathe after walking about 100 yards or after a few
              minutes on the level

  4           Too breathless to leave the house or breathless when dressing
              or undressing
  ----------- ---------------------------------------------------------------

8.  Has not received systemic corticosteroid and/or high-dose inhaled
    corticosteroid therapy for at least 6 weeks prior to the Screening
    Visit. High dose inhaled corticosteroids are defined as:

-   Beclomethasone dipropionate ≥1008 mcg/day

-   Triamcinolone acetonide ≥1600 mcg/day

-   Flunisolide ≥2000 mcg/day

-   Fluticasone propionate MDI ≥880 mcg/day

-   Fluticasone propionate Diskus ≥1000 mcg/day

-   Budesonide ≥1600 mcg/day

9.  Able to tolerate a 2-week run-in period during which the following
    medications were discontinued:

-   Inhaled corticosteroids

-   Ipratropium

-   Nedocromil sodium and cromolyn sodium

-   Anti-leukotriene agents

-   Intranasal steroids

-   Any beta-agonist other than Ventolin

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-   Theophylline, unless at a stable dosage for one month

10. Able to complete a diary card and subject questionnaires

11. Able to effectively use the Diskus and MDI inhalers, spirometry
    equipment, and mini-Wright peak flow meter

12. Provide a signed, dated, and witnessed informed consent

*[Reviewer comment:]{.underline}*

*The sponsor's paraphrasing of the ATS definition of COPD places an
emphasis on reversibility. While reversible obstruction does occur in
the COPD population, it should not be considered central to the
definition. The process underlying COPD is one of progressive loss of
lung tissue, leading primarily to structural obstruction as opposed to
functional^1-4^. The select nature of the subjects recruited for this
study leads to serious concerns about the generalizability of its
results to the COPD population as a whole. The ATS definition follows:*

> *"COPD is defined 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."^1^*

*The inclusion criteria allow for patients who were receiving fairly
large doses of inhaled corticosteroids prior to enrollment. This may
have the effect of enriching the study for patients who were responsive
to inhaled corticosteroids, as one would expect patients with no
response or a poor response to have their treatment discontinued.*

### Exclusion criteria

Exclusion criteria for this study are listed below. These reflect
protocol amendments. \[clinstat\\copd\\flta3025.pdf, pages 5278-5281,
5372, 5399\]:

1.  Current diagnosis of asthma in accordance with the ATS
    definition^1^:

-   Increased responsiveness of the tracheobronchial tree

-   Paroxysms of dyspnea, wheezing, and cough, which may vary from mild
    and almost undetectable to severe and unremitting

-   Primary physiological manifestation of hyperresponsiveness is
    variable airway obstruction

-   Variability may be manifest in improvements of obstruction following
    bronchodilators or corticosteroids or increased obstruction caused
    by drugs or other stimuli

2.  Requirement for any of the following medications:

-   Beta-blockers

-   Digitalis

-   Ketoconazole, fluconazole

-   Monoamine oxidase inhibitors

-   Phenothiazines

-   Immunosuppressive agents including cyclosporine, methotrexate, and
    gold

-   Use of inhaled short-acting bronchodilator within 6 hours prior to
    screening

-   Use of any short acting form of oral beta-agonist, short-acting form
    of theophylline or other bronchodilator within 12 hours prior to
    screening

-   Use of any twice daily form of an inhaled or oral beta-agonist or
    controlled-release form of theophylline within 48 hours of screening

3.  Requirement for pulmonary rehabilitation

4.  A respiratory disorder other than COPD (e.g., lung cancer,
    bronchiectasis, sarcoidosis, tuberculosis, lung fibrosis); history
    of lobectomy within one year of the screening visit.

5.  Requirement for a continuous positive pressure device

6.  Any significant concurrent diseases that would place the subject at
    risk, interfere with clinical evaluations, or influence study
    participation, including but not limited to:

-   History of pathologic fractures

-   Clinically significant cardiac disease

-   Symptomatic or clinically significant pathological fractures

-   Systemic arterial hypertension if the subject is poorly compliant
    with medications, likely to require frequent changes in medication
    during the study period, or requires therapy with beta-blockers

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```
-   Hepatic disease

-   Renal disease requiring dialysis or at risk of requiring dialysis
    within 6 months of screening

-   Neurologic disease

-   Uncontrolled hyperthyroidism or hypothyroidism

-   Diabetes mellitus that is either poorly controlled or complicated by
    significant renal or cardiovascular disease

-   Severe hematologic disease

-   Active peptic ulcer

-   Disorders of humoral or cellular immunity

-   Cushing's disease

-   Addison's disease

-   Presence of glaucoma requiring treatment with non-selective
    beta-blockers

-   History of malignancy

-   Inadequately controlled psychiatric illness

-   Mental retardation

-   Peripheral vascular disease

7.  Requirement for supplemental oxygen with the following exceptions:

-   Lives at an altitude above 3000 feet and does not require more than
    2 L of oxygen per minute for more than 12 hours per day

-   Does not require more than 2 L of oxygen per minute for exertion for
    more than 12 hours per day

8.  A known or suspected hypersensitivity to inhaled corticosteroids,
    beta-agonists or lactose. Gastrointestinal lactose intolerance is
    not an exclusion criterion.

9.  A known or suspected history of alcohol or drug abuse within the
    previous two years

10. 12-lead ECG at screening is abnormal and clinically significant

11. A moderate or severe exacerbation of COPD during the run-in period

12. Chest X-ray reveals clinically significant abnormalities not
    believed to be due to the presence of COPD

13. Received an investigational drug within 30 days prior to entry into
    the run-in period

14. A participating investigator, sub-investigator, study coordinator,
    or employee of a participating investigator, or an immediate family
    member of the aforementioned

15. An abnormal and clinically significant laboratory test a the
    screening visit which is still abnormal on repeat analysis

16. Previous participation in a fluticasone and/or salmeterol study via
    the Diskus for COPD

*[Reviewer comment:]{.underline}*

*The sponsor uses an ATS definition of asthma from 1987. This definition
makes no reference to the role of inflammation in asthma. A more
appropriate and up-to-date definition might be the National Asthma
Education and Prevention Program (NAEPP) definition of asthma, which
refers to the role of inflammation as well as reversible airway
obstruction^9^. Taken strictly, this exclusion criterion would exclude
all patients who have reversible airway obstruction, and that clearly
did not occur during this study.*

### Protocol amendments

There were four protocol amendments, dated 7/1/98, 7/27/98, 7/22/98, and
12/14/98 \[clinstat\\copd\\flta3025.pdf, page 5396\] . The third
protocol amendment was a substudy protocol for genotyping during the
study. This substudy will not be reviewed.

*[Reviewer comment:]{.underline}*

*The most notable change to the protocol was included in Protocol
Amendment 4. The FEV~1~/FVC ratio required for entry into the study was
changed from ≤65% to ≤70% \[clinstat\\copd\\flta3025.pdf, page 5399\].
The effect of this change would be to allow entry of patients with both
those with milder obstruction (who would be perhaps more likely to have
reversibility) and those with very severe obstruction with accompanying
air trapping. This amendment was made after the study had been started.
The inclusion criteria specifying the FEV~1~ and the level of dyspnea
will minimize any impact of this change. Protocol amendments otherwise
included minor changes to wording and study design that were likely to
have little impact on the evaluation of efficacy or safety.*

### Study procedures

Study procedures are displayed in Table 11.1.1. Patients provided an
informed consent, and received a medical history and physical
examination at the screening visit. Chest X-ray, pregnancy test,
screening labs, and ECGs were performed. Spirometry with assessment of
reversibility was also performed. Reversibility was assess by performing
spirometry 30 minutes after patient self-administration of 4 puffs of
Ventolin MDI without a spacer or holding chamber
\[clinstat\\copd\\flta3025.pdf, page 5288\].

There was a two-week, single-blind, run-in period for patients meeting
entrance criteria. Patients had all concurrent inhaled or oral
bronchodilator treatment discontinued and were given Ventolin MDI or
nebules to be used as needed for duration of the trial, including the
run-in. Patients received placebo via the Diskus BID during the run-in,
and baseline observations were made for peak expiratory flow rates
(PEFR), Ventolin use, and night-time awakenings that required Ventolin
use \[clinstat\\copd\\flta3025.pdf, pages 5275\]. The purpose of the
single-blind run-in period was to establish baseline pulmonary function
and diary card data for at least 10 of the 14 days. Patient compliance
with medication and recording of diary data was also assessed
\[clinstat\\copd\\flta3025.pdf, page 5288\]. Patient were to record
daily morning PEFRs, nighttime awakenings requiring Ventolin use, use of
rescue Ventolin, and any medical problems experienced
\[clinstat\\copd\\flta3025.pdf, pages 5289\].

Criteria for patients to be eligible for randomization included the
following \[clinstat\\copd\\flta3025.pdf, pages 5289\]:

-   Satisfaction of inclusion and exclusion criteria

-   At least 70% compliant with study medication during the run-in

-   Completed diary data for at least 10 of the 14 days of the run-in

-   Had not started or stopped smoking during the run-in

-   Proficiency in use of the peak flow meter

-   Able to safely withhold prohibited study medications

Patients who completed the run-in period and met all randomization
criteria were assigned to one of three double-blind treatments via the
Diskus for 24 weeks:

-   FP 250 mcg BID

-   FP 500 mcg BID

-   Placebo BID

According to the study protocol, assignment to study drug was to be
stratified according to the patients' response to reversibility testing
with Ventolin at screening to a non-reversible group and a reversible
group. Non-reversible patients were defined as having an absolute volume
increase \<200 mL or an absolute volume increase of ≥200 mL with
baseline FEV~1~ reversibility of \<12%. Reversible patients were defined
as having an absolute volume increase ≥200 mL with baseline FEV~1~
reversibility of ≥12% \[clinstat\\copd\\flta3025.pdf, pages 5283; IND
44,090 N134 PN, 8/4/98, page 25\].

*[Reviewer comment:]{.underline}*

*The definition of reversibility is critical for this study. In
addition, the proportion of patients with reversible obstruction is also
critical, even if the proportion in each of the three treatment groups
is similar. FP clearly is effective for treatment of asthma, and
inclusion of a high proportion of patients with a significant degree of
reversibility would be likely to result in an overstatement of efficacy
for the entire group. Although assignment to study drug was stratified
according to reversibility based on the above definition, no analysis
was planned or provided for these subgroups. Instead, subgroup analysis
was provided for subgroups based on a different definition of
reversibility. This issue and its effects are discussed in Section
11.1.17.1 of this document, "Data sets analyzed".*

Patients were evaluated weekly for the first four weeks of treatment,
every two weeks until week 8, and then every four weeks for the
remainder of the study. Patients who developed an exacerbation could be
treated with antibiotic therapy as an outpatient for two exacerbations,
but were discontinued from the study if a third exacerbation occurred.
Subjects with exacerbations requiring treatment with systemic
corticosteroids were to be discontinued from the study.

Patient evaluations at each of the clinic visits included spirometry.
Symptoms were also evaluated with the Baseline/Transition Dyspnea Index
(BDI/TDI), Chronic Bronchitis Symptom Questionnaire (CBSQ), and
assessment of the severity of any COPD exacerbations since the last
evaluations. Health outcomes were assessed with the Chronic Respiratory
Disease Questionnaire (CRDQ), a health-related quality of life
instrument \[clinstat\\copd\\flta3025.pdf, pages 5291-5294\]. The
BDI/TDI, CBSQ, and CRDQ instruments and the instrument for assessment of
COPD exacerbations are described below in Section 1.1.12, Assessment of
signs and symptoms.

Patients completed diary cards during the treatment period. Patients
measured PEFRs in triplicate prior to the morning dose of study
medication. The highest of 3 PEFR values was recorded on diary card.
Patients also were to record nighttime awakenings requiring Ventolin
use, the use of supplemental Ventolin, any medical problems, any need
for other concomitant medication, and AEs
\[clinstat\\copd\\flta3025.pdf, pages 5293-5294\].

Table 11.1.1. Study outline, FLTA3025 \[clinstat\\copd\\flta3025.pdf,
page 5322\].

<table>
<colgroup>
<col style="width: 19%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td><strong>Screen</strong></td>
<td><strong>Run-in</strong></td>
<td colspan="11"><strong>Double-blind treatment period</strong></td>
<td><strong>DC</strong></td>
</tr>
<tr class="even">
<td><strong>Visit number</strong></td>
<td></td>
<td></td>
<td><strong>1</strong></td>
<td><strong>2</strong></td>
<td><strong>3</strong></td>
<td><strong>4</strong></td>
<td><strong>5</strong></td>
<td><strong>6</strong></td>
<td><strong>7</strong></td>
<td><strong>8</strong></td>
<td><strong>9</strong></td>
<td><strong>10</strong></td>
<td><strong>11</strong></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Treatment Day/Week</strong></td>
<td></td>
<td><p><strong>Day</strong></p>
<p><strong>–14 to 1</strong></p></td>
<td><strong>Day 1</strong></td>
<td><strong>Wk 1</strong></td>
<td><strong>Wk 2</strong></td>
<td><strong>Wk 3</strong></td>
<td><strong>Wk 4</strong></td>
<td><strong>Wk 6</strong></td>
<td><strong>Wk8</strong></td>
<td><strong>Wk 12</strong></td>
<td><strong>Wk 16</strong></td>
<td><strong>Wk 20</strong></td>
<td><strong>Wk 24</strong></td>
<td></td>
</tr>
<tr class="even">
<td>Informed consent</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Medical history</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Smoking cessation counseling</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Chest X-ray</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Physical examination</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Pregnancy test</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Reversibility test</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Review inhalation technique</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Medical Research Council Questionnaire</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Clinical laboratory tests</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>12-lead ECG and rhythm strip</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Vital signs</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Oropharyngeal exam</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Review smoking status</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>AE detection</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Spirometry testing</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Exacerbation assessment</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Dispense/review diary card</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>BDI/TDI dyspnea scale</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Quality of life questionnaire</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>PK and serum cortisol samples</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Dispense PEFR devices and Ventolin MDI/nebules</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Dispense study medication</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Concurrent medication assessment</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Discharge from study</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
</tbody>
</table>

### Allowable concurrent medications

Allowable concurrent medications included
\[clinstat\\copd\\flta3025.pdf, page 5284\]:

-   Inhaled Ventolin MDI and/or nebules, provided by the sponsor for use
    as relief medication. Ventolin was to be withheld for at least 6
    hours prior to each treatment visit.

-   Antibiotics were permitted for treatment of two exacerbations.
    Patients were dropped from the study if a third COPD exacerbation
    occurred.

-   Antidepressants other than MAO inhibitors

-   Theophylline, if on a stable dose for at least one month prior to
    screening

### Prohibited medications

The following medications were prohibited
\[clinstat\\copd\\flta3025.pdf, page 5285\]:

-   Any oral, intranasal, or inhaled corticosteroids other than the
    study medication

-   Beta-agonists other than the Ventolin supplied by the sponsor

-   Concurrent use of any other prescription or over-the-counter
    medication which may affect the course of COPD or interact with
    study medications. These medications were to be discontinued at
    least 2 weeks prior to randomization.

### Drug product and placebo

The sponsor provided the following study treatments
\[clinstat\\copd\\flta3025.pdf, pages 43-44\]:

-   Placebo Diskus, for the single-blind run-in period and 24-week
    treatment period

-   FP Diskus 250 mcg one puff BID for the 24-week double-blind study
    period

-   FP Diskus 500 mcg one puff BID for the 24-week double-blind study
    period

-   Ventolin MDI and nebules for each subject as rescue medication

*[Reviewer comment:]{.underline}*

*The FP Diskus 500 mcg is not an approved product. The sponsor has
argued dose proportionality of the 250 mcg and 500 mcg products in
another study included in this submission. The interpretation of these
dose proportionality data is a review issue discussed elsewhere in this
review, and discussed in depth in the clinical pharmacology review.*

Study drug was packaged in identically appearing Diskus devices to blind
treatments \[clinstat\\copd\\flta3025.pdf, page 46\]. The batch numbers
of medication were used in this study are displayed in Table 11.1.2.

Table 11.1.2. Batch numbers of study medication, FLTA3025
\[clinstat\\copd\\flta3025.pdf, page 44\].

+-----------------------------------+-----------------------------------+
| **Product**                       | **Batch numbers**                 |
+===================================+===================================+
| Placebo Diskus                    | WP1WF9                            |
|                                   |                                   |
|                                   | WP25L4                            |
+-----------------------------------+-----------------------------------+
| FP Diskus 250 mcg                 | U98/028A                          |
+-----------------------------------+-----------------------------------+
| FP Diskus 500 mcg                 | U98/024C                          |
+-----------------------------------+-----------------------------------+
| Ventolin MDI, 90 mcg/puff         | 8ZP0692                           |
|                                   |                                   |
|                                   | 8ZP0909                           |
|                                   |                                   |
|                                   | 8ZP1741                           |
|                                   |                                   |
|                                   | 8ZP1924                           |
|                                   |                                   |
|                                   | 8ZP1924                           |
|                                   |                                   |
|                                   | 9ZP0124                           |
+-----------------------------------+-----------------------------------+
| Ventolin nebules, 0.098%, 2.5     | 970963                            |
| mg/3 mL                           |                                   |
|                                   | 980904                            |
|                                   |                                   |
|                                   | 980905                            |
|                                   |                                   |
|                                   | 980911                            |
|                                   |                                   |
|                                   | 980901                            |
+-----------------------------------+-----------------------------------+

The sponsor states that the formulations of Flovent used in this study
were representative of the commercial product in terms of input
materials, scale of manufacture, manufacturing equipment, and
manufacturing process. The only differences between the batches of
Flovent that were supplied for this study and the commercial product
were the device coloration and the overwrap. All batches of Ventolin
nebules and Ventolin MDI used in this study were the approved commercial
product. The placebo used in this study was identical to the active
product used in this study except for the absence of active drug \[NDA
20-833, SE1-004, 9/17/01, page 3; NDA 20-833, SE1-004, 12/5/01, page
1\].

### Assessment of compliance

Patient compliance with the drug dosing schedule was determined from the
dose counter on the Diskus devices. Patients who were less than 70%
compliant with the use of study medication during the 2-week run-in were
dropped from the study \[clinstat\\copd\\flta3025.pdf, pages 46, 66\].

### Assessment of signs and symptoms

Patient COPD symptoms were evaluated with the Chronic Bronchitis Symptom
Questionnaire (CBSQ), Baseline/Transition Dyspnea Index (BDI/TDI), and
assessment of the severity of any COPD exacerbations since the last
evaluations. These instruments are described below.

The CBSQ was composed of selected questions from the Petty Subject
Evaluation Questionnaire^10^ and the Revised Global Petty Questionnaire
for Ease of Cough and Sputum Clearance^11^. The CBSQ evaluated cough
frequency and severity, sputum release, and chest discomfort on a 0 to
4, 5-point scale. Individual scores were summed to provide a Global
Assessment Score (GAS). As noted in the inclusion criteria, patients
must have had a GAS of ≥4 at Treatment Day 1 to qualify for the study
\[clinstat\\copd\\flta3025.pdf, pages 48-49\].

Additional data describing the CBSQ were included with the application.
These data describe the administration of the CBSQ. The patient was
allowed to read each question along with the interviewer and verbally
select the response that best described the status of that particular
symptom on a typical day during the past week. After reading the
question, as written, with the subject, the interviewer used discussion
questions and observations to assist the subject in providing as precise
an answer as possible \[clinstat\\other\\cbsqvalidationdocument.pdf,
page 6\]. A Minimally Clinically Important Change (MCIC) for the CBSQ
was determined to be a change from baseline of 1.4 in the GAS
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 11\]. The
calculation of the MCIC assessed the change in GAS for individual
subjects by collecting them into one of four categories to assess a
Global Rating of Change (GRC)
\[clinstat\\other\\cbsqvalidationdocument.pdf, pages 8-9\]:

1.  GRC = 0, ±1: No change in symptoms of chronic bronchitis

2.  GRC = ±2, ±3: A minimal change in symptoms of chronic bronchitis

3.  GRC = ±4, ±5: A moderate change in symptoms of chronic bronchitis

4.  GRC = ±6, ±7: A large change in symptoms of chronic bronchitis

However the validation package indicates that there was poor correlation
between the GAS and the GRC used to calculate the MCIC. Pearson and
Spearman's correlation coefficients between GAS and GRC were only from
0.25 to 0.34 \[clinstat\\other\\cbsqvalidationdocument.pdf, page 9\].
Furthermore, large standard deviations in the GRC and MCIC were noted.
The standard deviations were large enough for each of the GRC categories
to substantially overlap each other
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 11\].

*[Reviewer comment:]{.underline}*

*The CBSQ was administered in such a fashion that the interviewer might
have influenced patient responses. The poor correlation between the GAS
and GRC and the large standard deviation in the GRC indicate that the
MCIC is not likely to be valid. This instrument will not be able to
provide support for the efficacy of FP. Furthermore, this instrument was
validated in a subset of patients from within this same study, FLTA3025
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 8\].*

The BDI/TDI was used to provide a clinical measurement of baseline and
change in dyspnea. The degree of functional impairment at baseline due
to dyspnea, the magnitude of task to provoke dyspnea, and the magnitude
of effort that provoked dyspnea were rated on a 0 to 4, 5-point scale to
derive the BDI. Changes from baseline in functional impairment,
magnitude of task, and magnitude of effort were assessed at each
subsequent visit with a -3 to +3, seven-point scale, the TDI
\[clinstat\\copd\\flta3025.pdf, pages 49-54\].

The sponsor provided a reference for this instrument that showed a weak
correlation of the BDI with FEV~1~, FVC, and the 12-minute walk distance
with correlation coefficients of 0.41, 0.56, and 0.60^12^. TDI
correlated only weakly with change in the change in the 12-minute walk
distance, with a correlation coefficient of 0.33. There was no
correlation of TDI with change in FEV~1~ or change in FVC. The sponsor
considered a change from BDI to TDI of 1.0 to be clinically relevant
\[clinstat\\copd\\flta3025.pdf, page 67, Correspondence submitted to IND
50,703, Meeting request package, 2/6/98\]. The sponsor did not include a
validation package with this application or with the meeting request
package of 2/6/98.

*[Reviewer comment:]{.underline}*

*Degree of functional impairment, magnitude of task, and magnitude of
effort are likely to be highly correlated variables, in this reviewer's
opinion, and therefore will tend to inflate any observed positive or
negative treatment effect. This instrument will not be likely to provide
support for the efficacy of FP.*

The investigator assessed the severity of any COPD exacerbations at each
clinic visit using a three-level scale, mild to severe. Mild
exacerbations were defined as use of more than 12 puffs or 4 nebules of
relief bronchodilator per day for more than 2 consecutive days, but
without the need for additional medication. Moderate exacerbations were
defined as requiring either antibiotics or corticosteroids. Severe
exacerbations were defined as requiring inpatient admission for
treatment \[clinstat\\copd\\flta3025.pdf, pages 54-55\].

*[Reviewer comment:]{.underline}*

*This is not the standard definition of COPD exacerbation. In fact, this
definition describes situations that reflect a worsening of airway
bronchoconstriction. This definition of exacerbation would be likely to
favor the finding of efficacy of FP in patients who have a high degree
of reversibility. The most widely accepted definition of COPD
exacerbation follows^5^:*

-   *Type 1 = All of the following symptoms*

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-   *Increased dyspnea, increased sputum volume, increased sputum
    purulence*

```{=html}
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```
-   *Type 2 = Two of the following symptoms*

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```
-   *Increased dyspnea, increased sputum volume, increased sputum
    purulence*

```{=html}
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```
-   *Type 3 = One of the following symptoms*

```{=html}
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```
-   *Increased dyspnea, increased sputum volume, increased sputum
    purulence and one of the following:*

```{=html}
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```
-   *URI within 5 days, fever without non-respiratory cause, increased
    wheezing, increased coughing, increase in respiratory rate of heart
    rate ≥20%*

Patients were to complete diary records during the treatment period each
morning. Patients recorded the highest of three PEFRs measurements
performed each morning prior the dose of study medication, the number of
inhalations of supplemental Ventolin use over the preceding 24 hours,
and the number of nighttime awakenings requiring the use of Ventolin
during the preceding night \[clinstat\\copd\\flta3025.pdf, page 55\].

### Health-related quality of life instrument

Health outcomes were assessed with the Chronic Respiratory Disease
Questionnaire (CRDQ), a health-related quality of life instrument^13^
\[clinstat\\copd\\flta3025.pdf, pages 55-56\]. The sponsor states that
the instrument is an interviewer-administered, disease-specific,
validated, questionnaire designed to measure the impact of chronic
respiratory disease and its treatments on the patient's COPD-related
quality of life. The CRDQ is a 20-item questionnaire that evaluates
health-related quality of life across four domains---dyspnea, fatigue,
emotional function, and mastery over the disease. The responses for each
of the 20 items were summed to provide an overall assessment of
health-related quality of life. A physical score was calculated based on
the sum of scores of the dyspnea and fatigue domains and an emotional
score was calculated based on the sum of the scores of the emotional
function and mastery domains. The CRDQ was completed at Day 1, and Weeks
2, 4, 8, 24, and Discontinuation.

### Efficacy variables 

Efficacy variables for this study are described below.

#### Primary efficacy variable

The primary efficacy variable for this study was the pre-dose FEV~1~
collected at Day 1, and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. The
primary analysis was the endpoint analysis comparing the mean morning
pre-dose FEV~1~ between treatment groups. The endpoint was defined in
the protocol as the final evaluable measurement for the patient. For
patients who discontinued from the study the endpoint was the last
evaluable measurement taken prior to withdrawal
\[clinstat\\copd\\flta3025.pdf, page 5301\]. Therefore, the FEV~1~ at
the Discontinuation Visit was not used for any efficacy analysis. The
sponsor's rationale for not using the FEV~1~ at the Discontinuation
Visit was that patients might have stopped taking study drug prior to
the visit and might have been taking another drug known to affect
results \[clinstat\\copd\\flta3025.pdf, page 66\].

*[Reviewer comment:]{.underline}*

*The sponsor's concern about possible confounding of efficacy results as
a result of FEV~1~ values at the Discontinuation visit is acknowledged.
However, the sponsor's plan to carry the last measurement from the
preceding visit forward for discontinuing patients also affects the
interpretation of efficacy results. Demonstration of efficacy of FP will
be more difficult if the rate of withdrawals due to treatment failure is
higher in the placebo group than in the FP groups. Demonstration of
efficacy of FP will be easier if the rate of withdrawals is similar
among all treatment groups or are higher in the FP groups.*

Treatment groups were compared using ANCOVA F-tests with baseline,
treatment group, and investigator as covariates. Mean morning pre-dose
FEV~1~ was also compared between treatment groups at each treatment
visit as an additional analysis \[clinstat\\copd\\flta3025.pdf, page
5301\].

#### Secondary efficacy variables

Secondary efficacy variables included change from baseline in the global
and individual domains of the CBSQ, the BDI/TDI score at each of the
treatment visits, number and percent of exacerbations of COPD, time to
first COPD exacerbation, number of withdrawals and time to withdrawals.
Morning PEFR, daily use of Ventolin, percentage of nights with no
awakenings requiring Ventolin, frequency of nighttime awakenings
requiring Ventolin, and percent of days without using Ventolin were also
summarized.

Summary statistics were provided for all secondary endpoints. Changes
from baseline in the Global Assessment Score (GAS) of the CBSQ were
compared between treatment groups using an ANCOVA F-test with baseline
value as covariate. Overall and pairwise treatment comparisons of the
BDI/TDI scores were performed by ANOVA F-test, Time to first COPD
exacerbation, number of withdrawals, and time to withdrawals were
analyzed using survival analysis. \[clinstat\\copd\\flta3025.pdf, page
5303\].

The CRDQ was also used to compare changes in the COPD-related quality of
life for treatment groups, as measured by an overall score and for each
of the four domains. An improvement of at least 10 in overall score was
considered to be an overall improvement in COPD specific quality of
life. At each visit, treatment group comparisons were made comparing the
change from baseline using ANOVA, controlling for baseline and
investigator. A difference between treatment groups in mean change from
baseline was considered clinically meaningful if the difference was
statistically significant and had a minimum of ≥0.5 point improvement
per question per item \[clinstat\\copd\\flta3025.pdf, page 5304\].

### Pharmacokinetics and pharmacodynamics

Blood samples for plasma FP and serum cortisol analyses were obtained at
Week 4 at selected sites. Samples were to be collected immediately prior
to dosing and at 0.5, 1, 2, 4, 8, and 12 hours post-dose
\[clinstat\\copd\\flta3025.pdf, page 5298\]. Plasma was analyzed for PF
concentration at each time point using solid phase extraction in
combination with liquid chromatography tandem mass spectrometry. The
sponsor states that this method has been validated to a limit of
quantitation of 10 pg/mL for FP \[clinstat\\copd\\flta3025.pdf, page
60\].

### Safety variables

Safety variables for this study included AEs, ECGs, hematology and
clinical chemistry studies, oropharyngeal examinations, and vital signs
\[clinstat\\copd\\flta3025.pdf, page 5294\]. Summary statistics were to
be provided for each of the safety endpoints
\[clinstat\\copd\\flta3025.pdf, page 5305\].

*[Reviewer comment:]{.underline}*

*Although the safety variables are appropriate to assess the local and
systemic safety of FP, it would have been preferable to have formal
ophthalmologic examinations and assessments of bone density.*

### Statistical considerations

Imputation of missing data was planned for the primary efficacy
parameter and the humanistic outcomes. Last observation carried forward
analysis was to be performed. \[clinstat\\copd\\flta3025.pdf, page
5367\].

#### Data sets analyzed

The primary population for the analysis of both efficacy and safety was
the intent-to-treat population, defined as all randomized subjects who
received at least one dose of study drug \[clinstat\\copd\\flta3025.pdf,
page 5300\].

The sponsor planned a subgroup analysis for patients who have an
increase in percent predicted FEV~1~ of less than 10% after albuterol at
the screening visit. This group was called the "non-reversible-percent
of predicted patients" \[clinstat\\copd\\flta3025.pdf, page 5300; IND
44,090 N134 PN, 8/4/98, page 42\].

*[Reviewer comment:]{.underline}*

*This is apparently a typographic error, as this group is referred to as
the "poorly-reversible population" in the study report
\[clinstat\\copd\\flta3025.pdf, page 62\]. This analysis was to be
provided to support the approval of the product outside the US
\[clinstat\\copd\\flta3025.pdf, page 90; IND 44,090 N134 PN, 8/4/98,
page 41\]. The sponsor indicates that this definition reflects current
opinion of the European Respiratory Society \[NDA 20-833, SE1-004, pages
1-2, 8/10/01\].*

*As noted earlier in this document, assignment to study drug was to be
stratified according to the patients' response to reversibility testing
with bronchodilator at screening to non-reversible and reversible
groups. The non-reversible group was defined earlier in the protocol as
patients with an absolute volume increase of \<200 mL or absolute volume
increase ≥200 mL with baseline reversibility assessment of \<12% , and
is based on the ATS definition of reversibility
\[clinstat\\copd\\flta3025.pdf, page 5283; IND 44,090 N134 PN, 8/4/98,
page 25; NDA 20-833, SE1-004, pages 1-2, 8/10/01\]. The proportion of
patients with reversibility will be critical to determine if the
population studied accurately reflects the population of patients with
COPD.*

*Assignment to study drug was stratified depending on whether patients
were reversible (FEV~1~ increase of ≥200 mL and ≥12% improvement in
FEV~1~ over baseline) or non-reversible (FEV~1~ increase \<200 mL or
\<12% improvement in FEV~1~ over baseline), i.e., the ATS definition. As
noted earlier, the sponsor did not initially provide a subgroup analysis
for the non-reversible population with the original submission. The
sponsor submitted in response to an information request by the
Division.*

*The sponsor provided an extensive subgroup analysis of the
"poorly-reversible population." As noted above, the "poorly-reversible
population" was defined as those patients who had an increase in percent
predicted FEV~1~ of less than 10% after albuterol at the screening
visit. Although this may be the accepted definition for the ERS, it is a
curious way of expressing reversibility, as it uses a theoretical value
as the baseline (percent predicted FEV~1~), rather than an actually
measured value, such as FEV~1~ at baseline. The ERS definition and the
subgroup analysis of the poorly reversible population are not relevant
to approval of this drug for this indication in the US, however, and
this subgroup analysis will receive only brief review.*

The sponsor made no adjustment for multiple comparisons for any efficacy
endpoint. The sponsor's reason was that there was only one primary
efficacy endpoint \[clinstat\\copd\\flta3025.pdf, page 63\].

*[Reviewer comment:]{.underline}*

*This review will examine only the primary efficacy endpoint
inferentially. This review will examine other efficacy endpoints
numerically, as inferential analysis is appropriate for prospectively
defined efficacy endpoints that have been corrected for multiple
comparisons.*

#### Statistical power

The sponsor calculated that a sample size of 145 patients per treatment
arm would be necessary to provide \>80% power to detect a clinically
meaningful significant difference of 0.1 liter between treatment groups.
The sponsor assumed a standard deviation for the change from baseline
FEV~1~ of 0.3 liters, and a level of significance of 0.05, using a
two-sample t-test. The sponsor planned to enroll an additional 55
subjects per treatment arm for a separate analysis of patients with
airway reversibility \<10% in predicted FEV~1~. Therefore, the sponsor
planned to randomize 600 patients with a total of 200 patients per
treatment arm \[clinstat\\copd\\flta3025.pdf, page 5299\].

### Results

#### Populations enrolled/analyzed

There were 1030 patients screened for the study. There were 390 patients
who were screening failures. A total of 640 patients were randomized.
The most common reason for screening failure was FEV~1~ /FVC \<70% and
baseline FEV~1~ \<65% predicted but \>0.7 L (237/390, 61%). Other
reasons for screening failure included inability to tolerate the 2-week
run-in (29/390, 7%), abnormal and clinically significant 12-lead ECG
(23/390, 6%), MMRC ≤2 (18/390, 5%), and significant concurrent disease
(17/390, 4%) \[clinstat\\copd\\flta3025.pdf, pages 74, 1002-1005\].

*[Reviewer comment:]{.underline}*

*One might expect that failure to tolerate the 2-week run-in would be
the most common reason for screening failure in this study. However,
inability to meet the inclusion criterion for spirometry was the most
common reason for screening failure. This is probably the reason for the
change in Protocol Amendment 4 that changed FEV~1~ /FVC ratio from ≤65%
to ≤70%. The most likely effect of this change would be to allow entry
of patients with milder obstruction. These patients might be more likely
to have reversibility, and might be more likely to respond and inhaled
corticosteroid such as FP.*

Patient disposition is summarized in Table 11.1.3. There were a total of
640 patients randomized and 414 patients completed the study. There were
226 patients that discontinued the study prematurely. There were more
discontinuations in the placebo group (79/206, 38%) than in the FP 250
group (76/216, 35%) or the FP 500 group (71/218, 22%). The most frequent
reason for discontinuation for all groups was COPD exacerbation. Among
patients discontinuing the study, there were 32 patients (41%, 32/79)
who discontinued due to an occurrence reported as COPD exacerbation in
the placebo group compared with 22 patients (29%, 22/76) in the FP 250
group and 20 patients (28%, 20/71) in the FP 500 group. Adverse events
(AEs) leading to discontinuation were most common in the FP 500 group
and were less common in the FP 250 and placebo groups. Lack of efficacy
was a more frequent reason for discontinuation in the FP 250 (18%) and
placebo (13%) groups than in the FP 500 group (6%)
\[clinstat\\copd\\flta3025.pdf, pages 75, 288\].

*[Reviewer comment:]{.underline}*

*COPD exacerbations and lack of efficacy in the FP 250 and placebo
groups give some weak support to the efficacy of FP 500. It should be
noted that the most common reason for discontinuation in the FP 500
group was an AE.*

Protocol violations included use of prohibited medications, cessation of
smoking, use of the wrong Diskus during the run-in period, or diagnosis
of another medical condition during the study
\[clinstat\\copd\\flta3025.pdf, pages 1441-1448\].

*[Reviewer comment:]{.underline}*

*Protocol violations were fairly infrequent and evenly distributed
between treatment groups and were not likely to affect the analysis of
efficacy or safety.*

Table 11.1.3. Patient disposition, FLTA3025,
\[clinstat\\copd\\flta3025.pdf, pages 75, 288\]

+----------------------+-----------+-----------+-----------+-----------+
|                      | **        | **FP      | **FP      | **Total** |
|                      | Placebo** | 250**     | 500**     |           |
|                      |           |           |           | **N (%)** |
|                      | **N (%)** | **N (%)** | **N (%)** |           |
+----------------------+-----------+-----------+-----------+-----------+
| Patients randomized  | 206 (100) | 216 (100) | 218 (100) | 640 (100) |
+----------------------+-----------+-----------+-----------+-----------+
| Patients completed   | 127 (62)  | 140 (65)  | 147 (67)  | 414 (65)  |
+----------------------+-----------+-----------+-----------+-----------+
| Patients             | 79 (38)   | 76 (35)   | 71 (33)   | 226 (35)  |
| discontinued         |           |           |           |           |
+----------------------+-----------+-----------+-----------+-----------+
| Reason for           |           |           |           |           |
| discontinuation      |           |           |           |           |
+----------------------+-----------+-----------+-----------+-----------+
| Adverse event        | 14 (18)   | 13 (17)   | 18 (25)   | 45 (20)   |
+----------------------+-----------+-----------+-----------+-----------+
| COPD exacerbation    | 32 (41)   | 22 (29)   | 20 (28)   | 74 (33)   |
+----------------------+-----------+-----------+-----------+-----------+
| Withdrawn consent    | 7 (9)     | 2 (3)     | 8 (11)    | 17 (8)    |
+----------------------+-----------+-----------+-----------+-----------+
| Lack of efficacy     | 10 (13)   | 18 (24)   | 4 (6)     | 32 (14)   |
+----------------------+-----------+-----------+-----------+-----------+
| Lost to follow-up    | 3 (4)     | 4 (5)     | 3 (4)     | 10 (4)    |
+----------------------+-----------+-----------+-----------+-----------+
| Protocol violation   | 10 (13)   | 14 (18)   | 14 (20)   | 38 (17)   |
+----------------------+-----------+-----------+-----------+-----------+
| Death                | 1\* (\<1) | 0 (0)     | 0 (0)     | 1 (\<1)   |
+----------------------+-----------+-----------+-----------+-----------+
| Other                | 3 (4)     | 3 (4)     | 4 (6)     | 10 (4)    |
+----------------------+-----------+-----------+-----------+-----------+

\*Patient with ovarian adenocarcinoma discovered 17 days after final
study visit, not included in total for discontinuations.

#### Protocol deviations

There were few patients who deviated from the protocol who were not
discontinued from the study. These included patients who did not meet
entry criteria at randomization (Table 11.1.4) or who had variations
from the protocol during the study (Table 11.1.5). The most common
protocol deviations due to variation from entry criteria were
insufficient severity of disease or significant concurrent disease
(Table 11.1.4). The most common protocol variation during the study was
use of medication that interfered with objective assessments (Table
11.1.5) \[clinstat\\copd\\flta3025.pdf, pages 74-75, 292-295,
1492-1496\].

Table 11.1.4. Protocol deviations due to failure to meet entry criteria
\[clinstat\\copd\\flta3025.pdf, page 76\].

+---------------------+---------------+---------------+---------------+
|                     | **Placebo**   | **FP 250**    | **FP 500**    |
|                     |               |               |               |
|                     | **N = 206**   | **N = 216**   | **N = 218**   |
|                     |               |               |               |
|                     | **n (%)**     | **n (%)**     | **n (%)**     |
+=====================+===============+===============+===============+
| Inclusion criteria  | 8 (4)         | 10 (5)        | 5 (2)         |
+---------------------+---------------+---------------+---------------+
| Severity of disease | 4 (2)         | 8 (4)         | 4 (2)         |
+---------------------+---------------+---------------+---------------+
|                     |               |               |               |
+---------------------+---------------+---------------+---------------+
| Exclusion criteria  | 15 (7)        | 10 (5)        | 11 (5)        |
+---------------------+---------------+---------------+---------------+
| Significant         | 7 (3)         | 4 (2)         | 3 (1)         |
| concurrent disease  |               |               |               |
+---------------------+---------------+---------------+---------------+
| Concurrent          | 3 (1)         | 2 (\<1)       | 4 (2)         |
| medications         |               |               |               |
+---------------------+---------------+---------------+---------------+
| Drug or alcohol     | 4 (2)         | 1 (\<1)       | 0 (0)         |
| abuse               |               |               |               |
+---------------------+---------------+---------------+---------------+

Table 11.1.5. Protocol deviations during conduct of the study
\[clinstat\\copd\\flta3025.pdf, page 295\].

+---------------------+---------------+---------------+---------------+
|                     | **Placebo**   | **FP 250**    | **FP 500**    |
|                     |               |               |               |
|                     | **N = 206**   | **N = 216**   | **N = 218**   |
|                     |               |               |               |
|                     | **n (%)**     | **n (%)**     | **n (%)**     |
+=====================+===============+===============+===============+
| All protocol        | 14 (7)        | 19 (9)        | 17 (8)        |
| deviations\*        |               |               |               |
+---------------------+---------------+---------------+---------------+
| Used tobacco        | 1 (\<1)       | 0 (0)         | 2 (\<1)       |
+---------------------+---------------+---------------+---------------+
| Used a prohibited   | 5 (2)         | 5 (2)         | 4 (2)         |
| corticosteroid      |               |               |               |
+---------------------+---------------+---------------+---------------+
| Used other          | 7 (3)         | 11 (5)        | 7 (3)         |
| prohibited          |               |               |               |
| medication          |               |               |               |
+---------------------+---------------+---------------+---------------+
| Other               | 5 (2)         | 13 (6)        | 10 (5)        |
+---------------------+---------------+---------------+---------------+

\*Some patients had more than one protocol deviation, therefore totals
within columns do not equal the total of all deviations.

#### Demographic and background characteristics

Demographics and background characteristics of patients are displayed in
Table 11.1.6. The majority of patients in each of the treatment groups
were 65 years of age or older. The mean age of patients was 64 years in
the placebo group, 65 years in the FP 250 group, and 63 years in the FP
500 group. Patients ranged from 39 to 88 years of age. The proportion of
patients aged 65 years or greater was similar in each of the treatment
groups. The mean age and age range was similar in each of the treatment
groups.

The majority of patients in this study were of male gender. Males
represented from 66% to 72% of patients in each of the treatment groups.
The distribution of male and female patients was similar in each of the
treatment groups. The vast majority of patients in this study were of
Caucasian race, approximately 95%. There were very few patients of Black
or Asian race. Non-Caucasian races represented less than 5% of each of
the treatment groups.

Patients in this study had fairly severe dyspnea. All patients
experienced dyspnea with walking on level ground, and approximately one
third of the patients in each of the treatment groups had dyspnea with
walking on level ground for 100 yards or worse (MMRC Dyspnea Score ≥3).
Patients had a history of COPD for approximately 7 years. Duration of
COPD ranged from 1 year to 45 years. The majority of patients were
former smokers, but a fairly large minority of patients were current
smokers. Median history of smoking was approximately 50 pack-years in
each of the treatment groups, much larger than the 20 pack-year history
required for entry into the study.

Approximately 30% of each of the treatment groups used inhaled
corticosteroids at the time of screening. Patients using inhaled
corticosteroid at the time of screening were evenly distributed among
the treatment groups.

The majority of patients in each treatment group had emphysema. The
frequency of emphysema was similar among treatment groups and ranged
from 74% to 81%.

*[Reviewer comments:]{.underline}*

*The under-representation of non-Caucasian patients in this study is a
deficiency. The lack of Black, Asian, and Hispanic patients will make it
impossible to assess efficacy or safety by race. The degree of dyspnea,
duration of COPD, smoking status, and magnitude of smoking history were
similar among treatment groups. The population studied is characterized
by long smoking histories and significant dyspnea.*

*A fairly large minority of the patients was taking inhaled
corticosteroids at the time of screening. As noted earlier in this
review, one would expect these patients to more likely to be
corticosteroid-responsive than those not taking inhaled corticosteroids,
as one would expect patients with no response or a poor response to have
their treatment discontinued. It would be preferable to perform the
study on corticosteroid-naïve patients.*

Table 11.1.6. Demographics, FLTA3025 \[clinstat\\copd\\flta3025.pdf,
pages 78, 296-300\].

+-------------------+----------------+----------------+----------------+
| *                 | **Placebo**    | **FP 250**     | **FP 500**     |
| *Characteristic** |                |                |                |
|                   | **N = 206**    | **N = 216**    | **N = 218**    |
+===================+================+================+================+
| **Age, years**    | **n (%)**      | **n (%)**      | **n (%)**      |
+-------------------+----------------+----------------+----------------+
| \<65              | 97 (47)        | 93 (43)        | 111 (51)       |
+-------------------+----------------+----------------+----------------+
| ≥65               | 109 (53)       | 123 (57)       | 107 (49)       |
+-------------------+----------------+----------------+----------------+
| Mean age          | 64.8           | 65.2           | 63.3           |
+-------------------+----------------+----------------+----------------+
| SD                | 9.5            | 8.7            | 10.0           |
+-------------------+----------------+----------------+----------------+
| Range             | 42 -- 87       | 40 -- 88       | 39 -- 85       |
+-------------------+----------------+----------------+----------------+
|                   |                |                |                |
+-------------------+----------------+----------------+----------------+
|                   |                |                |                |
+-------------------+----------------+----------------+----------------+
| **Gender**        | **n (%)**      | **n (%)**      | **n (%)**      |
+-------------------+----------------+----------------+----------------+
| Female            | 66 (32)        | 60 (28)        | 74 (34)        |
+-------------------+----------------+----------------+----------------+
| Male              | 140 (68)       | 156 (72)       | 144 (66)       |
+-------------------+----------------+----------------+----------------+
|                   |                |                |                |
+-------------------+----------------+----------------+----------------+
| **Race**          | **n (%)**      | **n (%)**      | **n (%)**      |
+-------------------+----------------+----------------+----------------+
| Caucasian         | 196 (95)       | 204 (94)       | 206 (94)       |
+-------------------+----------------+----------------+----------------+
| Black             | 6 (3)          | 9 (4)          | 9 (4)          |
+-------------------+----------------+----------------+----------------+
| Asian             | 0 (0)          | 1 (\<1)        | 1 (\<1)        |
+-------------------+----------------+----------------+----------------+
| Other             | 4 (2)          | 2 (\<1)        | 2 (\<1)        |
+-------------------+----------------+----------------+----------------+
|                   |                |                |                |
+-------------------+----------------+----------------+----------------+
| **MMRC Dyspnea    | **n (%)**      | **n (%)**      | **n (%)**      |
| Score**           |                |                |                |
+-------------------+----------------+----------------+----------------+
| 2                 | 138 (67)       | 141 (65)       | 140 (64)       |
+-------------------+----------------+----------------+----------------+
| 3                 | 62 (30)        | 70 (32)        | 68 (31)        |
+-------------------+----------------+----------------+----------------+
| 4                 | 6 (3)          | 5 (2)          | 10 (5)         |
+-------------------+----------------+----------------+----------------+
|                   |                |                |                |
+-------------------+----------------+----------------+----------------+
| **Duration of     | **Years**      | **Years**      | **Years**      |
| COPD**            |                |                |                |
+-------------------+----------------+----------------+----------------+
| Mean              | 7.35           | 8.39           | 7.74           |
+-------------------+----------------+----------------+----------------+
| Range             | 1 -- 45        | 1 -- 43        | 1 -- 39        |
+-------------------+----------------+----------------+----------------+
|                   |                |                |                |
+-------------------+----------------+----------------+----------------+
| **Smoking         | **n (%)**      | **n (%)**      | **n (%)**      |
| status**          |                |                |                |
+-------------------+----------------+----------------+----------------+
| Former smoker     | 118 (57)       | 119 (55)       | 115 (53)       |
+-------------------+----------------+----------------+----------------+
| Current smoker    | 88 (43)        | 97 (45)        | 103 (47)       |
+-------------------+----------------+----------------+----------------+
|                   |                |                |                |
+-------------------+----------------+----------------+----------------+
| **Pack-years      |                |                |                |
| smoked**          |                |                |                |
+-------------------+----------------+----------------+----------------+
| Median            | 50             | 54.5           | 52.3           |
+-------------------+----------------+----------------+----------------+
| Range             | 20 -- 168      | 20 -- 157      | 20 -- 201      |
+-------------------+----------------+----------------+----------------+
|                   |                |                |                |
+-------------------+----------------+----------------+----------------+
| **Inhaled         | **n (%)**      | **n (%)**      | **n (%)**      |
| steroids at       |                |                |                |
| screening**       |                |                |                |
+-------------------+----------------+----------------+----------------+
| Yes               | 64 (31)        | 66 (31)        | 68 (31)        |
+-------------------+----------------+----------------+----------------+
| No                | 142 (69)       | 150 (69)       | 150 (69)       |
+-------------------+----------------+----------------+----------------+
|                   |                |                |                |
+-------------------+----------------+----------------+----------------+
| **Emphysema**     | **n (%)**      | **n (%)**      | **n (%)**      |
+-------------------+----------------+----------------+----------------+
| Yes               | 160 (78)       | 175 (81)       | 161 (74)       |
+-------------------+----------------+----------------+----------------+
| No                | 46 (22)        | 41 (19)        | 57 (26)        |
+-------------------+----------------+----------------+----------------+

Patients had fairly severe airway obstruction. Spirometry results at the
time of screening are presented in Table 11.1.7. The mean FEV~1~ for
each treatment group of about 1250 mL, mean FEV~1~ % predicted of about
40%, and mean FEV~1~/FVC % of about 47%. The degree of airway
obstruction was similar in each of the treatment groups
\[clinstat\\copd\\flta3025.pdf, page 305\].

*[Reviewer comment:]{.underline}*

*The severity of airway obstruction observed is not unexpected given the
fairly severe level of dyspnea reported by patients.*

Table 11.1.7. Spirometry at screening, FLTA3025
\[clinstat\\copd\\flta3025.pdf, page 305\].

+-----------------------+--------------+--------------+--------------+
|                       | **Placebo**  | **FP 250**   | **FP 500**   |
|                       |              |              |              |
|                       | **n = 206**  | **n = 216**  | **n = 218**  |
+-----------------------+--------------+--------------+--------------+
| **FEV~1~, mL**        |              |              |              |
+-----------------------+--------------+--------------+--------------+
| Mean                  | 1254         | 1242         | 1266         |
+-----------------------+--------------+--------------+--------------+
| SD                    | 450          | 449          | 430          |
+-----------------------+--------------+--------------+--------------+
| Median                | 1130         | 1155         | 1160         |
+-----------------------+--------------+--------------+--------------+
| Range                 | 470 -- 2790  | 640 -- 2730  | 610 -- 2750  |
+-----------------------+--------------+--------------+--------------+
|                       |              |              |              |
+-----------------------+--------------+--------------+--------------+
| **FEV~1~, %           |              |              |              |
| predicted**           |              |              |              |
+-----------------------+--------------+--------------+--------------+
| Mean                  | 40.97        | 39.75        | 41.27        |
+-----------------------+--------------+--------------+--------------+
| SD                    | 11.79        | 11.76        | 12.23        |
+-----------------------+--------------+--------------+--------------+
| Median                | 40.45        | 38.79        | 41.08        |
+-----------------------+--------------+--------------+--------------+
| Range                 | 16.8 -- 64.4 | 17.8 -- 66.5 | 18.0 -- 68.5 |
+-----------------------+--------------+--------------+--------------+
|                       |              |              |              |
+-----------------------+--------------+--------------+--------------+
| **FEV~1~/FVC %**      |              |              |              |
+-----------------------+--------------+--------------+--------------+
| Mean                  | 47.19        | 46.62        | 47.78        |
+-----------------------+--------------+--------------+--------------+
| SD                    | 10.29        | 10.04        | 10.25        |
+-----------------------+--------------+--------------+--------------+
| Median                | 47.44        | 45.92        | 47.83        |
+-----------------------+--------------+--------------+--------------+
| Range                 | 16.7 -- 70.5 | 21.5 -- 69.1 | 25.0 -- 69.1 |
+-----------------------+--------------+--------------+--------------+

Patient response to treatment with bronchodilator at screening is
summarized in Table 11.1.8. A patient was considered "non-reversible"
if, after 4 puffs of Ventolin MDI, there was a change in FEV~1~ of \<12%
from baseline or there was \<200 mL absolute increase in the FEV~1~.
Reversible patients represented 59% of all patients in this study. The
mean % change in FEV~1~ for reversible patients was 32.4%.
Non-reversible patients represented 41 % of all patients in this study.
The mean % change in FEV~1~ for non-reversible patients was 9.24%. The
degree of reversibility in each of the treatment groups was similar. The
mean % change in FEV~1~ for all patients was 22.9%.

*[Reviewer comment:]{.underline}*

*The proportion of patients enrolled in the study with reversibility is
much higher than is found in the population of COPD patients at large.
There were 59% of patients in this study who had reversibility. One
would expect that only up to 30% of patients to have in increase of ≥15%
in FEV~1~ after inhalation of a beta-agonist.^1,\ 3^ In addition, the
degree of reversibility for the reversible population is high---32.43%.
The mean degree of reversibility in the non-reversible population was
also high---9.24%.*

*The high proportion of patients with reversibility in this study is a
critical consideration in determining whether the results of the study
can be generalized to the COPD population as a whole. Reversible
patients were over-represented relative to their prevalence in the COPD
population as a whole^1,\ 2^, and the degree of reversibility in these
patients is much higher than would be expected for the general
population of patients with COPD^1,2^. Enrichment for these highly
reversible patients would be predicted to increase the effect size.
While not a "fatal flaw" in this study, it does argue for restricted
labeling, should the indication be granted, and against a broad "COPD"
indication.*

*Although the sponsor stratified for reversible and non-reversible
populations at randomization, initially the sponsor did not perform an
analysis of efficacy for these subgroups. The subgroup analysis was
provided by the sponsor in response to a request for information, and is
reviewed in Section 11.1.18.7.*

**Table 11.1.8. Mean change in FEV~1~** after bronchodilator treatment
at screening\*, FLTA3025 \[clinstat\\copd\\flta3025.pdf, pages
306-307\].

  --------------------------------------------------------------------------
                     **Placebo**   **FP 250**    **FP 500**    **All
                                                               treatment
                                                               groups**
  ------------------ ------------- ------------- ------------- -------------
  **Reversible                                                 
  patients**                                                   

  n (%)              122 (60)      127 (59)      124 (57)      373 (59)

  Mean % change in   31.54         32.20         33.54         32.43\*\*
  FEV~1~                                                       

  **Non-reversible                                             
  (ATS) patients**                                             

  n (%)              83 (40)       87 (41)       92 (43)       262 (41)

  Mean % change in   10.08         8.10          9.56          9.24\*\*
  FEV~1~                                                       

  **All patients**                                             

  n (%)              205 (100)     214 (100)     216 (100)     635 (100)

  Mean % change in   22.85         22.40         23.33         22.86\*\*
  FEV~1~                                                       
  --------------------------------------------------------------------------

\*Calculation of response: ([Post-BD FEV]{.underline}~1~ [minus Pre-BD
FEV]{.underline}~1~[) X 100]{.underline}

Pre-BD FEV~1~

> Not reversible if result is \<12% or \<200 mL increase in FEV~1~

Reversible if result is ≥12% and ≥200 mL increase in FEV~1~

\*\*Mean change derived from data for individual treatment group data

Compliance with study treatment is displayed in Table 11.1.9. More than
70% of patients in each treatment group took 90% or more of the
prescribed doses of medication. The mean number of doses taken was
approximately 93% in each treatment group
\[clinstat\\copd\\flta3025.pdf, pages 81, 361\].

*[Reviewer comment:]{.underline}*

*Compliance seemed adequate to allow for assessment of efficacy and
safety, given the trial design, although current compliance assessments
are notoriously unreliable.*

Table 11.1.9. Compliance with study treatment, FLTA3025
\[clinstat\\copd\\flta3025.pdf, pages 81, 361\].

+-----------------+-----------------+-----------------+-----------------+
|                 | **Placebo**     | **FP 250**      | **FP 500**      |
|                 |                 |                 |                 |
|                 | **n (%)**       | **n (%)**       | **n (%)**       |
+=================+=================+=================+=================+
| All patients    | 206 (100)       | 216 (100)       | 218 (100)       |
+-----------------+-----------------+-----------------+-----------------+
| \<80%           | 17 (8)          | 9 (4)           | 21 (10)         |
| compliance      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| 80-\<90%        | 37 (18)         | 35 (16)         | 39 (18)         |
| compliance      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| ≥90% compliance | 151 (73)        | 170 (79)        | 156 (72)        |
+-----------------+-----------------+-----------------+-----------------+
| Missing         | 1 (\<1)         | 2 (\<1)         | 2 (\<1)         |
+-----------------+-----------------+-----------------+-----------------+

#### Primary efficacy endpoint

The primary efficacy endpoint was the mean change in FEV~1~ from
Baseline to study endpoint. These data are displayed in Table 11.1.10.
Values for the mean change from baseline in FEV~1~ were small and were
75 mL or less. The mean change from baseline to endpoint in FEV~1~
compared to the placebo group for the FP 500 group was 50 mL. This
comparison was statistically significant at p = 0.010. This change
corresponds to an effect size of 4.0%[^1]. Mean change from baseline in
FEV~1~ compared to placebo was 27 mL for the FP 250 group. This
comparison was not statistically different from the placebo group. This
change corresponds to an effect size of 2.2%^1^. Values for the mean
change in FEV~1~ from Baseline for the FP 500 group at Weeks 6, 12, and
24 were small and ranged from 56 mL to 67 mL more than the placebo
group. Values for the mean change from baseline for the FP 250 group at
Weeks 6, 12, and 24 ranged from 20 to 29 mL more than the placebo group.
Values for the mean change from baseline for the placebo group at Weeks
6, 12, and 24 ranged from 3 to 11 mL.

Mean change from Baseline in FEV~1~ for the FP 500 group at Weeks 1, 2,
3, 4, 8, 16, and 20 showed changes of 101 mL or less
\[clinstat\\copd\\flta3025.pdf, pages 91, 427-436\]. Mean change from
baseline for the FP 250 group at Weeks 1, 2, 3, 4, 8, 16, and 20 showed
changes of 52 mL or less \[clinstat\\copd\\flta3025.pdf, pages 91,
427-436\]. Mean change from baseline for the placebo group at Weeks 1,
2, 3, 4, 8, 16, and 20 showed changes of 28 mL or less
\[clinstat\\copd\\flta3025.pdf, pages 91, 427-436\].

*[Reviewer comment:]{.underline}*

*Although there was a statistical significant difference from placebo
for the FP 500 group noted at endpoint and numerical superiority was
noted at the interim points, the absolute change in FEV~1~ is quite
small and of questionable clinical importance. The small size of this
change should be balanced against the high dose of inhaled
corticosteroid required to achieve this effect size and the highly
enriched patient population who showed reversibility with
bronchodilator.*

**Table 11.1.10. Mean change in FEV~1~ from baseline, primary efficacy
variable, FLTA3025 \[clinstat\\copd\\flta3025.pdf, pages 91,
427-436\].**

  ------------------ ------------- ----------- ------- --------- ----------- ------- --------- ----------- -------
                     **Placebo**                       **FP                          **FP                  
                                                       250**                         500**                 

  **Study week**     **Mean        **Mean      **n**   **Mean    **Mean      **n**   **Mean    **Mean      **n**
                     FEV~1~, mL**  change from         FEV~1~,   change from         FEV~1~,   change from 
                                   baseline,           mL**      baseline,           mL**      baseline,   
                                   mL**                          mL**                          mL**        

  **Baseline**       1203          NA          204     1207      NA          215     1246      NA          218

  **Week 6**         1248          11          164     1240      32          182     1325      67          191

  **Week 12**        1254          3           153     1248      23          161     1315      64          167

  **Week 24**        1275          8           125     1290      37          139     1319      75          146

  **Endpoint\*\***   1221          11          199     1240      38          211     1301      61          210

  p value vs.        Overall 0.035                     FP 250                        FP 500                
  placebo                                              vs. Pbo                       vs. Pbo               
                                                       0.140                         0.010                 
  ------------------ ------------- ----------- ------- --------- ----------- ------- --------- ----------- -------

\*ANCOVA, Baseline as covariate

\*\*Primary efficacy endpoint

#### Secondary efficacy endpoints

Secondary efficacy variables included change from baseline in the global
and individual domains of the CBSQ, the BDI/TDI score at each of the
treatment visits, number and percent of exacerbations of COPD, time to
first COPD exacerbation, number of withdrawals and time to withdrawals.
Morning PEFR, daily use of Ventolin, percentage of nights with no
awakenings requiring Ventolin, frequency of nighttime awakenings
requiring Ventolin, and percent of days without using Ventolin were also
summarized.

Summary statistics were provided for all secondary endpoints. The
sponsor provided an inferential statistical analysis of secondary
efficacy endpoints. Individual secondary efficacy endpoints are reviewed
below.

*[Reviewer comment]{.underline}:*

*Inferential analysis is appropriate only for the prospectively defined
efficacy endpoint on which the study was powered, and not for these
secondary efficacy endpoints. Therefore, this document will focus on the
numerical differences between treatment groups for the secondary
efficacy endpoints, and will not address the inferential statistical
analysis.*

##### Chronic Bronchitis Symptom Questionnaire

As noted earlier in this review, the CBSQ evaluated cough frequency and
severity, sputum release, and chest discomfort on a 0 to 4, 5-point
scale. Individual scores were summed to provide a Global Assessment
Score (GAS). The maximum possible GAS was 16. Patients were required to
have a minimum score of 4 at baseline to qualify for randomization. The
sponsor determined that the Minimally Clinically Important Change (MCIC)
in the CBSQ was 1.4 points in an analysis of patients completing at
least 8 weeks of this study
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 11\]. Results of the
Chronic Bronchitis Symptom Questionnaire are displayed in Table 11.1.11.
The sponsor reported decreases in the COPD for FP 250 and FP 500, but
the differences from placebo for these treatment groups were less than
the MCIC of 1.4 points \[clinstat\\copd\\flta3025.pdf, pages 91,
427-436\].

*[Reviewer comment:]{.underline}*

*The differences from placebo in the CBSQ for FP 250 and FP 500 were
less than the MCIC of 1.4 points.*

*The population studied included a high percentage of patients with
reversibility with bronchodilator and does not accurately represent the
population of COPD patients. As noted earlier in this review, the CBSQ
was administered in such a fashion that the interviewer might have
influenced patient responses. The poor correlation between the GAS and
GRC and the large standard deviation in the GRC lead to serious
questions about the design of this instrument and suitability for the
patient population. Of note, the CBSQ was "validated" using patients
from the same study (FLTA 3025) in which it was used as an endpoint,
which is clearly unacceptable. Furthermore, the differences from placebo
for FP 250 and FP 500 were less than the MCIC of 1.4 points. These data
will not be able to provide support for the efficacy of FP.*

**Table 11.1.11. Chronic Bronchitis Symptom Questionnaire, FLTA3025. See
text for comments on validity of this instrument
\[clinstat\\copd\\flta3025.pdf, pages 93, 440-445\].**

  -------------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ -------
                 **Pbo**                          **FP 250**                       **FP 500**               

  **Study week** **GAS\***   **Mean       **n**   **GAS\***   **Mean       **n**   **GAS\***   **Mean       **n**
                             change from                      change from                      change from  
                             baseline**                       baseline**                       baseline**   

  **Baseline**   7.1         NA           205     7.1         NA           215     7.4         NA           218

  **Week 1**     6.5         0.5          199     6.3         0.8          209     6.5         0.9          211

  **Week 2**     6.2         0.7          186     6.1         1.0          205     6.1         1.3          201

  **Week 3**     5.8         1.1          177     5.9         1.2          201     6.0         1.4          197

  **Week 4**     5.9         1.1          175     5.8         1.3          196     5.8         1.5          198

  **Week 6**     5.7         1.3          166     5.9         1.1          183     5.9         1.5          193

  **Week 8**     5.7         1.2          165     5.7         1.4          175     5.7         1.6          183

  **Week 12**    5.4         1.4          153     5.6         1.4          161     3.0         1.3          168

  **Week 16**    5.6         1.0          138     5.5         1.5          152     5.6         1.7          159

  **Week 20**    5.3         1.3          127     5.7         1.3          143     5.7         1.5          149

  **Week 24**    5.3         1.3          125     5.2         1.7          139     5.6         1.7          147

  **Endpoint**   6.1         0.9          199     5.7         1.4          211     6.0         1.4          211
  -------------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ -------

\*GAS: Global Assessment Score. Minimally clinically important change =
1.4 points.

##### Baseline/Transition Dyspnea Indices

The degree of functional impairment at baseline due to dyspnea, the
magnitude of task to provoke dyspnea, and the magnitude of effort that
provoked dyspnea were rated on a 0 to 4, 5-point scale to derive the
BDI. The maximum BDI score was 12. The TDI assessed changes from
baseline in functional impairment, magnitude of task, and magnitude of
effort were assessed at each subsequent visit with a -3 to +3,
seven-point scale \[clinstat\\copd\\flta3025.pdf, pages 49-54\]. The
sponsor considered a clinically important TDI score to be ≥1.0
\[clinstat\\copd\\flta3025.pdf, page 67, Correspondence submitted to IND
50,703, Meeting request package, 2/6/98\]. Results of the BDI/TDI are
presented in Table 11.1.12. The sponsor reported small clinically
significant TDIs for FP 500 endpoint and at all visits except Visit 1.
The sponsor reported small, clinically significant TDIs for FP 250 at
Weeks 8, 12, 16, and 24, but not at endpoint. The sponsor reported a
small clinically significant TDI for the placebo group was noted at Week
24. However, none of the TDIs for FP 250 or FP 500 were significantly
different from TDIs noted for placebo \[clinstat\\copd\\flta3025.pdf,
pages 94, 478-481\].

*[Reviewer comment:]{.underline}*

*The population studied included a high percentage of patients with
reversibility with bronchodilator and does not accurately represent the
population of COPD patients. Degree of functional impairment, magnitude
of task, and magnitude of effort are likely to be highly correlated
variables, in this reviewer's opinion, and therefore will tend to
inflate any observed positive or negative treatment effect. This
instrument has not been validated in a COPD population with a high
degree of reversibility, and it is not a widely used scale or one that
is held in high regard. These data do not provide support for the
efficacy of FP.*

**Table 11.1.12. Baseline/Transition Dyspnea Index, FLTA3025. See text
for comments on validity of this instrument
\[clinstat\\copd\\flta3025.pdf, pages 94, 478-481\].**

+---------+---------+---------+---------+---------+---------+---------+
|         | **Pbo** |         | **FP    |         | **FP    |         |
|         |         |         | 250**   |         | 500**   |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Study | **Bas   | **n**   | **Bas   | **n**   | **Bas   | **n**   |
| week**  | eline** |         | eline** |         | eline** |         |
|         |         |         |         |         |         |         |
|         | **      |         | **      |         | **      |         |
|         | score** |         | score** |         | score** |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Bas   | 5.8     | 204     | 6.3     | 213     | 5.9     | 216     |
| eline** |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
|         | **Trans |         | **Tra   |         | **Tra   |         |
|         | ition\* |         | nsition |         | nsition |         |
|         | Score** |         | Score** |         | Score** |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Week  | 0.1     | 199     | 0.4     | 209     | 0.8     | 211     |
| 1**     |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Week  | 0.2     | 186     | 0.7     | 204     | 1.0     | 201     |
| 2**     |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Week  | 0.3     | 177     | 0.7     | 200     | 1.0     | 197     |
| 3**     |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Week  | 0.4     | 175     | 0.8     | 196     | 1.0     | 198     |
| 4**     |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Week  | 0.6     | 166     | 0.9     | 183     | 1.2     | 193     |
| 6**     |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Week  | 0.6     | 165     | 1.0     | 175     | 1.5     | 183     |
| 8**     |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Week  | 0.6     | 152     | 1.1     | 161     | 1.2     | 168     |
| 12**    |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Week  | 0.7     | 138     | 1.1     | 152     | 1.5     | 159     |
| 16**    |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Week  | 0.8     | 127     | 0.9     | 143     | 1.5     | 149     |
| 20**    |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **Week  | 1.2     | 125     | 1.4     | 139     | 1.8     | 147     |
| 24**    |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| **End   | 0.5     | 199     | 0.9     | 211     | 1.2     | 211     |
| point** |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+

\*Minimally clinically significant TDI = 1.0 point.

##### COPD exacerbations

The incidence of COPD exacerbation was slightly lower for FP 250 and
FP500 than with placebo. This relationship was dose-related. The
incidence of moderate to severe COPD exacerbations was slightly lower
with FP 250 and FP 500 than placebo. This relationship was also
dose-related. Moderate to severe exacerbations of COPD were defined as
those requiring oral antibiotics, inhaled or oral corticosteroids, or
inpatient admission for treatment. These data are displayed in Table
11.1.13.

*[Reviewer comment:]{.underline}*

*The lower frequency of any COPD exacerbation, lower frequency of
moderate or severe COPD exacerbations, and dose ordering provide some
weak support for the efficacy of FP 250 and FP 500 for the population
studied. However, it is important to note that the definition of COPD
exacerbation was not the standard definition^1,\ 5,6.^ The sponsor's
definition of COPD exacerbation describes situations that reflect a
worsening of airway bronchoconstriction, and would be likely to favor
the finding of efficacy of FP in patients who have a high degree of
reversibility. Accordingly, any weak support for the efficacy of FP for
this endpoint is further weakened. In addition it should be noted that
the magnitude of the decrease in COPD exacerbations is quite small.*

Table 11.1.13. Incidence of COPD exacerbations, FLTA3025
\[clinstat\\copd\\flta3025.pdf, pages 96, 503-504\].

+------------------------+--------------+--------------+--------------+
|                        | **Placebo**  | **FP 250**   | **FP 500**   |
|                        |              |              |              |
|                        | **N = 206**  | **N = 216**  | **N = 218**  |
|                        |              |              |              |
|                        | **n (%)**    | **n (%)**    | **n (5)**    |
+------------------------+--------------+--------------+--------------+
| Patients with any COPD | 106 (51)     | 104 (48)     | 98 (45)      |
| exacerbation           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Patients with moderate | 88 (43)      | 87 (40)      | 83 (38)      |
| or severe COPD         |              |              |              |
| exacerbations          |              |              |              |
+------------------------+--------------+--------------+--------------+

Time to COPD exacerbation or withdrawal is summarized in Table 11.1.14.
In general, there were fewer first COPD exacerbations, first moderate to
severe COPD exacerbations, study withdrawals, and withdrawals due to
COPD exacerbation in the FP 250 and FP 500 groups than the placebo group
for each month of the study. In general, this tended to be a
dose-related observation, with most events in the placebo group,
followed next by the FP 250 group, with the least in the FP 500 group.

Table 11.1.14. Time to COPD exacerbation or withdrawal, FLTA3025

  --------------------------------- ------------ ------------ ------------ ------------ ------------ ------------
  **Time to First COPD Exacerbation                                                                  
  \[clinstat\\copd\\flta3025.pdf,                                                                    
  pages 506-508\]**                                                                                  

                                    **Pbo**                   **FP 250**                **FP 500**   

                                    **Patients   **Events**   **Patients   **Events**   **Patients   **Events**
                                    at risk**                 at risk**                 at risk**    

  Month 1                           149          45           174          36           173          33

  Month 2                           129          62           142          56           148          51

  Month 3                           107          82           118          75           130          67

  Month 4                           96           90           98           89           112          82

  Month 5                           84           99           86           98           97           94

  Month 6                           0            104          0            103          0            98

                                                                                                     

  **Time to First Moderate to                                                                        
  Severe COPD Exacerbation                                                                           
  \[clinstat\\copd\\flta3025.pdf,                                                                    
  pages 510-512\]**                                                                                  

                                    **Pbo**                   **FP 250**                **FP 500**   

                                    **Patients   **Events**   **Patients   **Events**   **Patients   **Events**
                                    at risk**                 at risk**                 at risk**    

  Month 1                           161          33           191          19           188          17

  Month 2                           141          49           162          35           162          35

  Month 3                           122          66           140          52           141          53

  Month 4                           110          74           116          69           122          69

  Month 5                           98           81           102          79           109          78

  Month 6                           0            86           0            86           0            83

                                                                                                     

  **Time to Study Withdrawal                                                                         
  \[clinstat\\copd\\flta3025.pdf,                                                                    
  pages 514-516508\]**                                                                               

                                    **Pbo**                   **FP 250**                **FP 500**   

                                    **Patients   **Events**   **Patients   **Events**   **Patients   **Events**
                                    at risk**                 at risk**                 at risk**    

  Month 1                           181          24           202          14           205          13

  Month 2                           170          35           182          35           192          26

  Month 3                           159          46           171          45           178          40

  Month 4                           147          58           158          57           169          49

  Month 5                           133          71           147          68           158          60

  Month 6                           0            76           0            72           0            70

                                                                                                     

  **Time to Study Withdrawal due to                                                                  
  COPD Exacerbation                                                                                  
  \[clinstat\\copd\\flta3025.pdf,                                                                    
  pages 518-520\]**                                                                                  

                                    **Pbo**                   **FP 250**                **FP 500**   

                                    **Patients   **Events**   **Patients   **Events**   **Patients   **Events**
                                    at risk**                 at risk**                 at risk**    

  Month 1                           181          12           202          6            205          1

  Month 2                           170          18           182          12           192          6

  Month 3                           159          25           171          18           178          14

  Month 4                           147          30           158          21           169          20

  Month 5                           133          36           147          26           158          22

  Month 6                           0            38           0            28           0            27
  --------------------------------- ------------ ------------ ------------ ------------ ------------ ------------

##### PEFR

Overall, there was a small mean increase from baseline in AM PEFR for
the FP 250 (8.8 L/min) and FP 500 (9.4 L/min) groups. A similar small
increase from baseline in AM PEFR was noted for FP 250 and FP 500 at the
end of each month during the treatment period. The increases were less
than 15 L/min for each of the FP treatment groups for each of the months
\[clinstat\\copd\\flta3025.pdf, page 97, 526-529\].

*[Reviewer comment:]{.underline}*

*The differences in mean AM PEFRs between treatment groups were quite
small, unlikely to be measurable in an individual patient, and are well
within the range of variation for this measurement. The absolute change
from baseline in FP 250 and FP 500 was \<4% and these differences are
not clinically significant.*

Table 11.1.15. Mean change from baseline in AM PEFR
\[clinstat\\copd\\flta3025.pdf, page 97, 526-529\]

  ------------------------ --------------- --------------- ---------------
                           **Placebo**     **FP 250**      **FP 500**

  **Baseline**                                             

  N                        205             213             218

  Mean PEFR, L/min         249.6           254.7           254.2

  **Overall**                                              

  N                        205             212             215

  Mean PEFR, L/min         247.5           262.3           263.8

  Mean change from         -1.9            8.8             9.4
  baseline, L/min                                          
  ------------------------ --------------- --------------- ---------------

##### Supplemental Ventolin use

Supplemental Ventolin use is summarized in Table 11.1.16. Overall, the
FP 250 and FP 500 groups had a small decrease in the number of puffs of
Ventolin used per day. This decrease was much less than one puff per
day. The decrease in Ventolin use for FP 250 and FP 500 for each study
month was never more than 0.3 puffs per day. Overall, the FP 250 and FP
500 groups had a small increase in the number of days without Ventolin
use, approximately 2%. The increase in days without Ventolin use for FP
250 and FP 500 for each study month was never more than 3.3% of days.

*[Reviewer comment:]{.underline}*

*The changes in Ventolin use are quite small and not clinically
significant.*

Table 11.1.16. Mean change from baseline in supplemental Ventolin use
\[clinstat\\copd\\flta3025.pdf, page 98, 526-529\]

+------------------------+--------------+--------------+--------------+
|                        | **Placebo**  | **FP 250**   | **FP 500**   |
+========================+==============+==============+==============+
| **Number of puffs of   |              |              |              |
| Ventolin used per      |              |              |              |
| day**                  |              |              |              |
+------------------------+--------------+--------------+--------------+
| **Baseline**           |              |              |              |
+------------------------+--------------+--------------+--------------+
| N                      | 205          | 213          | 218          |
+------------------------+--------------+--------------+--------------+
| Mean number of puffs   | 5.4          | 5.7          | 5.7          |
+------------------------+--------------+--------------+--------------+
| **Overall**            |              |              |              |
+------------------------+--------------+--------------+--------------+
| N                      | 204          | 212          | 215          |
+------------------------+--------------+--------------+--------------+
| Mean number of puffs   | 6.2          | 5.6          | 5.2          |
+------------------------+--------------+--------------+--------------+
| Mean change from       | 0.7          | -0.1         | -0.2         |
| baseline, puffs        |              |              |              |
+------------------------+--------------+--------------+--------------+
| **Percent of days      |              |              |              |
| without Ventolin use** |              |              |              |
+------------------------+--------------+--------------+--------------+
| **Baseline**           |              |              |              |
+------------------------+--------------+--------------+--------------+
| N                      | 205          | 213          | 218          |
+------------------------+--------------+--------------+--------------+
| Mean % days without    | 16.6         | 18.3         | 16.6         |
| Ventolin use           |              |              |              |
+------------------------+--------------+--------------+--------------+
| **Overall**            |              |              |              |
+------------------------+--------------+--------------+--------------+
| N                      | 204          | 212          | 215          |
+------------------------+--------------+--------------+--------------+
| Mean % days without    | 14.7         | 19.8         | 18.8         |
| Ventolin use           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Mean change from       | -1.7         | 2.0          | 2.1          |
| baseline,              |              |              |              |
|                        |              |              |              |
| \% days                |              |              |              |
+------------------------+--------------+--------------+--------------+

Nighttime awakenings requiring Ventolin use are summarized in Table
11.1.17. Overall, the FP 250 and FP 500 groups had a small decrease from
baseline in the number of awakenings per night. Overall the FP 250 and
FP 500 groups had a small increase in the percent of nights with no
awakenings requiring Ventolin use.

*[Reviewer comment:]{.underline}*

*The small changes from baseline in nighttime awakenings and percent of
nights with no awakenings requiring Ventolin are not clinically
significant.*

Table 11.1.17. Mean change from baseline in nighttime awakenings
requiring Ventolin use \[clinstat\\copd\\flta3025.pdf, pages 99-100\]

  ------------------------------------------------------------------------
                           **Placebo**     **FP 250**      **FP 500**
  ------------------------ --------------- --------------- ---------------
  **Number of awakenings                                   
  per night requiring                                      
  Ventolin**                                               

  **Baseline**                                             

  N                        202             212             217

  Mean number of           0.22            0.25            0.29
  awakenings                                               

  **Overall**                                              

  N                        202             211             212

  Mean number of           0.33            0.20            0.25
  awakenings                                               

  Mean change from         0.11            -0.05           -0.05
  baseline, awakenings                                     

  **Percent of nights with                                 
  no awakenings requiring                                  
  Ventolin**                                               

  **Baseline**                                             

  N                        202             212             217

  Mean % nights with no    84.0            82.2            81.7
  awakenings                                               

  **Overall**                                              

  N                        202             211             212

  Mean % nights with no    79.6            86.1            85.5
  awakenings                                               

  Mean change from         -4.3            4.2             3.4
  baseline, % nights with                                  
  no awakenings                                            
  ------------------------------------------------------------------------

##### Health-related quality of life instrument

COPD-related quality of life was evaluated using the Chronic Respiratory
Disease Questionnaire (CRDQ)^13^. The CRDQ contains 20 questions in 4
domains: dyspnea, fatigue, emotional function, and mastery. An overall
score, the sum of the scores for all 20 questions, was the primary
health-related quality of life endpoint. A physical score was calculated
based on the sum of scores in the dyspnea and fatigue domains and an
emotional score was calculated based on the sum of scores of the
emotional function and mastery domains \[clinstat\\copd\\flta3025.pdf,
page118\]. A clinically significant improvement was considered to be 0.5
points per item. Therefore, an improvement in the Overall score of at
least 10.0 points was considered to be a clinically significant
improvement in COPD-specific quality of life. As there were different
numbers of items per domain, the clinically significant changes for each
domain and summary scores are as follows \[clinstat\\copd\\flta3025.pdf,
pages 68-69, 118\]:

-   Fatigue domain: 2.0 points

-   Dyspnea domain: 2.5 points

```{=html}
<!-- -->
```
-   Physical summary: 4.5 points

```{=html}
<!-- -->
```
-   Emotional function domain: 3.5 points

-   Mastery domain: 2.0 points

-   Emotional summary: 5.5 points

Study endpoint was defined as the last available post-baseline score for
the CDRQ. This was different from the other analyses, which did not
include values for the Discontinuation visit
\[clinstat\\copd\\flta3025.pdf, page 118\]. In addition, the sponsor
excluded patients with an overall baseline score greater than 130 from
the analysis of the overall score at any visit. These patients were
excluded because baseline scores would be mathematically unable to
attain a clinically meaningful change \[clinstat\\copd\\flta3025.pdf,
page 119\]. Similar exclusions were made for the patients with the
following scores \[clinstat\\copd\\flta3025.pdf, page 118\]:

-   Fatigue score \>26

```{=html}
<!-- -->
```
-   Dyspnea score \>32

-   Physical summary \>58

-   Emotional function score \>45

-   Mastery score \>26

-   Emotional summary \>71

The population analyzed, which excluded these patients, was referred to
the "reduced intent-to-treat population" (reduced ITT population)
\[clinstat\\copd\\flta3025.pdf, page 119\].

*[Reviewer comment:]{.underline}*

*It is true that it is be mathematically impossible for patients whose
baseline scores are higher than those noted above to attain a clinically
meaningful change. However, the necessity to exclude a substantial
number of patients indicates that the instrument is inappropriate for
the patient population. This tends to reinforce this reviewer's
previously expressed concerns about how well the study population
reflects the overall COPD population. Nevertheless, it is not
appropriate to exclude these patients from the analysis. It would have
been preferable to set these maximum scores as inclusion criteria for
the study. As it turns out, there were no patients excluded for the
Overall score and the Emotional function summary score and the ITT and
"reduced ITT populations" were identical for these scores
\[clinstat\\copd\\flta3025.pdf, page 118-119\]. There were 22 patients
excluded from the calculation of the Emotional summary score, 23
patients from the Emotional domain score, 53 patients from the Mastery
domain score, 6 patients from the Fatigue domain score, and 2 patients
from the Dyspnea domain score, however. This review will examine CDRQ
results for the ITT group and not the reduced ITT population.*

Although there was a dose-related increase from baseline in the overall
CDRQ score for FP, this increase was less than the specified minimally
clinically significant change of 10.0 points. These data are displayed
in Table 11.1.18. Data displayed is for the ITT population. Dose-related
increases from baseline were also noted for FP 250 and FP 500 in the
Physical summary score and the Emotional summary score. Like the change
in the Overall score, the changes in these scores were less than the
specified minimally clinically significant changes, with the exception
of the Physical summary score for FP 500. There was less than a 4.5
point difference from the change from baseline for the placebo group for
the Physical summary score for FP 500, however, and therefore no
clinically significant difference from the placebo group
\[clinstat\\copd\\flta3025.pdf, pages 1256-1292\].

Individual domains showed similar small, dose-related, but not
clinically significant increases from baseline for FP 250 and FP 500,
with the exception of the Dyspnea domain, which showed a dose-related
clinically significant improvement from baseline for FP 250 and FP 500.
However, there was less than a 2.5 point difference from the change from
baseline for the placebo group for the Dyspnea domain scores, and
therefore no clinically significant difference from the placebo group
\[clinstat\\copd\\flta3025.pdf, pages 1256-1292\].

**Table 11.1.18. Chronic Respiratory Disease Questionnaire (CRDQ),
COPD-related quality of life instrument, ITT population, FLTA3025
\[clinstat\\copd\\flta3025.pdf, pages 1256-1292\].**

  --------------- ----------- ------------ ------- ----------- ------- ------------ ------- ----------- ------- ------------ -------
                  **Pbo**                                      **FP                                     **FP                 
                                                               250**                                    500**                

                  **Score**   **Mean       **n**   **Overall           **Mean       **n**   **Overall           **Mean       **n**
                              change from          score**             change from          score**             change from  
                              baseline**                               baseline**                               baseline**   

  **Overall                                                                                                                  
  score\***                                                                                                                  

  **Baseline**    87.6        NA           203     88.8                NA           214     83.6                NA           213

  **Endpoint**    89.6        1.0          199     94.2                5.1          211     92.8                9.1          210

  **Physical                                                                                                                 
  summary                                                                                                                    
  score\*\***                                                                                                                

  **Baseline**    33.3        NA           203     34.1                NA           214     32.6                NA           213

  **Endpoint**    34.9        1.2          199     37.8                3.7          211     37.4                4.8          210

  **Emotional                                                                                                                
  summary                                                                                                                    
  score\*\*\***                                                                                                              

  **Baseline**    54.3        NA           204     54.9                NA           215     51.0                NA           216

  **Endpoint**    54.7        -0.1         201     56.5                1.4          212     55.4                4.4          213
  --------------- ----------- ------------ ------- ----------- ------- ------------ ------- ----------- ------- ------------ -------

\*Clinically significant change in Overall Score = 10.0 points

\*\*Clinically significant change in Physical Summary Score = 4.5 points

\*\*\*Clinically significant change in Emotional Summary Score = 5.5
points

*[Reviewer comment:]{.underline}*

*The CRDQ is a widely used and well-validated instrument^13^. No
clinically significant change from baseline was observed in the Overall
score. In general, most of the individual domain and summary scores also
did not show clinical significance, and none showed a clinically
significant difference from the placebo group. As there was not a
clinically significant change in the Overall score, other changes in
individual domains or summary scores provide no meaningful information.
These data provide no support for the efficacy of FP 250 or FP 500 for
this population. More importantly, the small (50 mL) but "statistically
significant" increase in FEV~1~ noted for the primary endpoint is not
supported as being clinically important because there is no discernable
benefit to the patient that could be measured using this instrument.*

#### Smoking status, post-hoc subgroup analysis

The sponsor provided a post-hoc analysis of efficacy by patient smoking
status for exploratory purposes. Former smokers had the largest mean
change from baseline in FEV~1~ at endpoint. This finding was
dose-related \[clinstat\\copd\\flta3025.pdf, page 101\]. These data are
displayed in Table 11.1.19. Among the former smokers, those treated with
FP 500 had the largest change in FEV~1~ (100 mL), followed by those
treated with FP 250 (72 mL), and with the smallest change in those
treated with placebo (-5 mL). There were no meaningful differences in
the mean change from baseline in FEV~1~ between the treatment groups for
patients who were smokers during the conduct of the study.

Table 11.1.19. Mean change from baseline in FEV~1~ at endpoint, by
smoking status \[clinstat\\copd\\flta3025.pdf, page 101\].

+-----------------+-----------------+-----------------+-----------------+
| **Smoking       | **Placebo**     | **FP 250**      | **FP 500**      |
| status**        |                 |                 |                 |
|                 | **Mean change,  | **Mean change,  | **Mean change,  |
|                 | mL (n)**        | mL (n)**        | mL (n)**        |
+=================+=================+=================+=================+
| Current smokers | 31 (88)         | -5 (97)         | 17 (103)        |
+-----------------+-----------------+-----------------+-----------------+
| Former smokers  | -5 (118)        | 72 (119)        | 100 (115)       |
+-----------------+-----------------+-----------------+-----------------+

The sponsor also examined other efficacy endpoints by patient smoking
status. In general, where there were differences between the groups,
efficacy was favored in the former smokers. This was true for the CBSQ
and the BDI/TDI. Very small differences were noted in COPD
exacerbations, AM PEFR, Ventolin use, and nighttime awakenings were
noted favoring efficacy of FP 250 and FP 500 in the former smokers. The
magnitudes of these very small changes were similar to those noted for
the secondary efficacy endpoints. There were no meaningful differences
between the treatment groups for secondary efficacy endpoints for
patients who were smokers during the conduct of the study
\[clinstat\\copd\\flta3025.pdf, page 101\]. The Overall CRDQ score at
endpoint for former smokers in the FP 500 group showed a clinically
meaningful increase from baseline of 11.5 points. However, this increase
from baseline was not clinically meaningfully different from the
increase from baseline in the placebo group
\[clinstat\\copd\\flta3025.pdf, page 124\].

*[Reviewer comment:]{.underline}*

*Although these data are of a post-hoc exploratory nature, they strongly
suggest that patients who stopped smoking prior to the conduct of the
study carried the small amount of efficacy observed in the primary
endpoint. It has been well established by the Lung Health Study^8^ that
smoking cessation has a far greater impact on lung function and
long-term survival of the COPD patient than any pharmacological
intervention. It is therefore not unreasonable to attribute some of the
improvement in FEV~1~ observed during the study to abstention from
smoking.*

#### "Non-reversible" population, subgroup analysis

Assignment to study drug was to be stratified according to the patients'
response to reversibility testing with Ventolin at screening to a
non-reversible group and a reversible group. Non-reversible patients
were defined as having an absolute volume increase \<200 mL or an
absolute volume increase of ≥200 mL with baseline FEV~1~ reversibility
of \<12%. Reversible patients were defined as having an absolute volume
increase ≥200 mL with baseline FEV~1~ reversibility of ≥12%
\[clinstat\\copd\\flta3025.pdf, pages 5283; IND 44,090 N134 PN, 8/4/98,
page 25\]. Despite having assignment stratified based on
"non-reversibility," the sponsor did not initially include an analysis
for this subgroup. The sponsor was asked to provide a subgroup analysis
of the non-reversible group in an IR on 10/2/01. The sponsor submitted
this information in a document dated 1/17/01 \[NDA 20-833, SE1 004 BZ,
10/17/01\]. The results of the subgroup analysis for the non-reversible
population are briefly reviewed below.

Table 11.1.20 summarizes the mean change in FEV~1~ from baseline for the
"non-reversible" population. There was only a small change in FEV~1~
from baseline at study endpoint for FP 500 (21 mL), FP 250 (-15 mL) and
placebo (-17 mL). Changes of 28 mL and 13 mL were seen for FP 500 at
Weeks 12 and 24. Small increases from baseline were noted for FP 250 at
Weeks 12 and 24. Small decreases in FEV~1~ from baseline were noted for
placebo at Weeks 12 and 24 \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, page 18\].

**Table 11.1.20. Mean change in FEV~1~ from baseline, primary efficacy
variable, non-reversible population, FLTA3025 \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, page 18\].**

  -------------- ------------- ----------- ------- --------- ----------- ------- --------- ----------- -------
                 **Placebo**                       **FP                          **FP                  
                                                   250**                         500**                 

  **Study week** **Mean        **Mean      **n**   **Mean    **Mean      **n**   **Mean    **Mean      **n**
                 FEV~1~, mL**  change from         FEV~1~,   change from         FEV~1~,   change from 
                               baseline,           mL**      baseline,           mL**      baseline,   
                               mL**                          mL**                          mL**        

  **Baseline**   1151          NA          82      1153      NA          87      1175      NA          92

  **Week 12**    1218          -11         58      1150      -14         67      1263      28          68

  **Week 24**    1224          -25         49      1199      -2          51      1231      13          60

  **Endpoint**   1147          -17         80      1144      -15         86      1204      21          88
  -------------- ------------- ----------- ------- --------- ----------- ------- --------- ----------- -------

Response of the reversible population in the mean change in FEV~1~ from
baseline is summarized in Table 11.1.21. The difference from placebo for
mean change from baseline at endpoint for the reversible group for FP
500 was 64 mL and for FP 250 was 41 mL. This was greater than the
difference from placebo for mean change from baseline at endpoint for
the non-reversible group, which for FP 500 was 38 mL and for FP 250 was
2 mL \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, page 18\].

**Table 11.1.21. Mean change in FEV~1~ from baseline, primary efficacy
variable, reversible population, FLTA3025 \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, page 18\].**

  -------------- ------------- ----------- ------- --------- ----------- ------- --------- ----------- -------
                 **Placebo**                       **FP                          **FP                  
                                                   250**                         500**                 

  **Study week** **Mean        **Mean      **n**   **Mean    **Mean      **n**   **Mean    **Mean      **n**
                 FEV~1~, mL**  change from         FEV~1~,   change from         FEV~1~,   change from 
                               baseline,           mL**      baseline,           mL**      baseline,   
                               mL**                          mL**                          mL**        

  **Baseline**   1237          NA          122     1250      NA          126     1296      NA          124

  **Week 12**    1276          12          95      1326      50          92      1352      93          97

  **Week 24**    1308          29          76      1345      56          87      1388      119         85

  **Endpoint**   1271          29          119     1306      70          123     1204      93          120
  -------------- ------------- ----------- ------- --------- ----------- ------- --------- ----------- -------

In general, secondary endpoints demonstrated either no change or small,
clinically insignificant changes for FP 500 and FP 250 in the
non-reversible population. Changes in the GAS of the CBSQ or the TDI
showed no clinically meaningful changes for FP 250 or FP 500 in the non-
reversible population \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf,
page 18\]. The incidence and frequency of exacerbations due to COPD were
slightly lower in the FP 500 group than the FP 250 and placebo groups,
which had similar incidences and frequencies of COPD exacerbations. The
incidences and frequencies of moderate/severe COPD exacerbations were
similar across treatment groups for this population \[NDA 20-833 SE1
004, BZ, 10/17/01\\response.pdf, page 19\].

The probability of COPD exacerbation was lower during the first half of
the study in the FP groups compared with placebo, but by the end of the
study the FP 250 group and the placebo groups were similar \[NDA 20-833
SE1 004, BZ, 10/17/01\\response.pdf, page 23\]. In general, small and
clinically insignificant changes from baseline favoring FP 250 and FP
500 were noted in for the non-reversible population for the following
secondary endpoints: AM PEFR, number of puffs of Ventolin used per day,
and awakenings per night requiring Ventolin
\[clinstat\\copd\\flta3025.pdf, pages 20, 148, 156, 164\]. There were no
meaningful differences between treatment groups in the overall score of
the health-related quality of life instrument, the CRDQ \[NDA 20-833 SE1
004, BZ, 10/17/01\\response.pdf, page 169\]

*[Reviewer comment:]{.underline}*

*Analysis of the non-reversible population demonstrates little efficacy
in this population. Efficacy in this study was carried by those patients
in the reversible population.*

#### Pharmacokinetics and pharmacodynamics

Blood samples for plasma FP and serum cortisol analyses were obtained at
Week 4 at selected sites. Samples were to be collected immediately prior
to dosing and at 0.5, 1, 2, 4, 8, and 12 hours post-dose
\[clinstat\\copd\\flta3025.pdf, page 5298\]. Plasma was analyzed for FP
concentration at each time point using solid phase extraction in
combination with liquid chromatography tandem mass spectrometry. The
sponsor states that this method has been validated to a limit of
quantitation of 10 pg/mL for FP \[clinstat\\copd\\flta3025.pdf, page
60\].

*[Reviewer comment:]{.underline}*

*Unfortunately, baseline cortisol levels were not planned for this
study. Change in AM cortisol level or the AUC for cortisol from baseline
would have been more informative than these data derived from Week 4
samples alone.*

There were 86 patients who participated in the clinical pharmacology
component of this study. Of these 86 patients, 28 were treated with
placebo, 31 with FP 250, and 27 with FP 500
\[clinstat\\copd\\flta3025.pdf, page 166\]. The placebo group in the
PK/PD component was slightly older than the total study population (47%
\<65 years in the PK/PD population compared with 36% in the total study
population). There were fewer females in the placebo group of the PK/PD
component (14% in the PK/PD component vs. 32% in the total study
population). The PK/PD population had a slightly longer duration of COPD
in all treatment groups (approximately 8 to 10 years for the PK
populations vs. 7 to 8 years for the study population). Otherwise, the
PK/PD population was similar to that of the total study population in
demographics \[clinstat\\copd\\flta3025.pdf, pages 4889-4897\].

Key pharmacokinetic results are displayed in Table 11.1.22. FP AUC~last~
and FP C~max~ were higher for FP 500 than FP 250 and data suggest that 2
inhalations of FP 250 Diskus may be more than dose proportional than one
inhalation of FP 500 Diskus. Mean FP AUC~last~ was somewhat lower in
current smokers than in former smokers. In addition, a linear
relationship was observed between weight and FP AUC~last~ for FP 500,
with lower FP levels for heavier patients. This association was not
noted with FP 250 \[clinstat\\copd\\flta3025.pdf, pages 166, 4857,
4881\].

Table 11.1.22. Key pharmacokinetic results, FLTA 3025
\[clinstat\\copd\\flta3025.pdf, page 166\].

+-----------------------+-----------------------+-----------------------+
| **PK parameter**      | **FP 250**            | **FP 500**            |
|                       |                       |                       |
|                       | **N = 31**            | **N = 27**            |
+-----------------------+-----------------------+-----------------------+
| Mean AUC~last~,       | 310.6                 | 539.0                 |
| pg.hr/mL              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Mean C~max~, pg/ml    | 52.9                  | 83.6                  |
+-----------------------+-----------------------+-----------------------+

Key pharmacodynamic results are displayed in Table 11.1.23.

Table 11.1.23. Serum cortisol results, FLTA3025
\[clinstat\\copd\\flta3025.pdf, pages 166, 4855\].

+-----------------+-----------------+-----------------+-----------------+
| **Cortisol      | **Placebo**     | **FP 250**      | **FP 500**      |
| parameter**     |                 |                 |                 |
|                 | **N = 28**      | **N = 31**      | **N = 27**      |
+-----------------+-----------------+-----------------+-----------------+
| Mean Cortisol   | 2673.4          | 2404.2          | 2102.3          |
| AUC~12~,        |                 |                 |                 |
| pmol.hr/mL      | \-              | \- 10.1%        | \- 21.4%        |
|                 |                 |                 |                 |
| ∆ vs. placebo   |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Mean C~min~,    | 123.1           | 116.7           | 85.3            |
| pmol/mL         |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

FP 250 and FP 500 treatment groups had lower mean cortisol AUC~12~ and
mean C~min~ than the placebo group (10% and 21%, respectively, for serum
cortisol AUC). There was a dose-response effect noted with the lowest
cortisol AUC~12~ and C~min~ in FP 500 patients
\[clinstat\\copd\\flta3025.pdf, pages 166, 4855\]. Higher mean cortisol
AUC~12~ levels were noted for current smokers than for former smokers,
consistent with the lower serum FP levels measured in current smoking.
There was no relationship noted between cortisol levels and weight
\[clinstat\\copd\\flta3025.pdf, page 4857\].

*[Reviewer comment:]{.underline}*

*These PK and PD data demonstrate measurable systemic effects of inhaled
FP. These findings are not a surprise, given the large dose of FP used.
It is important to note this is clear evidence of systemic activity of
FP in this population, which is corroborated by the single dose
crossover study conducted in normal volunteers (see FLTA1003, OCPB
review). It should also be noted that these effects were noted early in
the course of the study, at Week 4. It would have been interesting to
examine similar data collected later in this study, for example, Week
24, where one might expect even a higher degree of suppression of
cortisol AUC~12~ levels. These data will influence any risk benefit
analysis of FP in this population, given the small treatment effect
noted.*

*It is interesting that lower FP AUC~last~ and higher cortisol AUC~12~
levels were seen in smokers, as one might expect increased FP absorption
in the presence of increased inflammation associated with smoking.*

#### Safety outcomes

In addition to serum cortisol AUC, discussed above, safety variables for
this study included AEs, ECGs, hematology and clinical chemistry
studies, oropharyngeal examinations, and vital signs
\[clinstat\\copd\\flta3025.pdf, page 5294\]. Each variable is discussed
below.

##### Total drug exposure

Total drug exposure is summarized in Table 11.1.24. Approximately 50% of
each group completed ≥24 weeks of study treatment. The mean duration of
treatment was 128.8 days for placebo, 133.2 days for FP 250, and 136.1
days for FP 250.

Table 11.1.24. Total drug exposure, FLTA3025
\[clinstat\\copd\\flta3025.pdf, pages 129, 801\].

+-----------------+-----------------+-----------------+-----------------+
| **Duration of   | **Placebo**     | **FP 250**      | **FP 500**      |
| treatment**     |                 |                 |                 |
|                 | **N = 206**     | **N = 216**     | **N = 218**     |
|                 |                 |                 |                 |
|                 | **n (%)**       | **n (%)**       | **n (%)**       |
+-----------------+-----------------+-----------------+-----------------+
| Any treatment   | 206 (100)       | 216 (100)       | 218 (100)       |
+-----------------+-----------------+-----------------+-----------------+
| ≥4 weeks        | 180 (87)        | 200 (93)        | 202 (93)        |
+-----------------+-----------------+-----------------+-----------------+
| ≥8 weeks        | 166 (81)        | 181 (84)        | 187 (86)        |
+-----------------+-----------------+-----------------+-----------------+
| ≥12 weeks       | 156 (76)        | 168 (78)        | 175 (80)        |
+-----------------+-----------------+-----------------+-----------------+
| ≥16 weeks       | 146 (71)        | 156 (72)        | 161 (74)        |
+-----------------+-----------------+-----------------+-----------------+
| ≥20 weeks       | 130 (63)        | 144 (67)        | 152 (70)        |
+-----------------+-----------------+-----------------+-----------------+
| ≥24 weeks       | 104 (50)        | 105 (49)        | 122 (56)        |
+-----------------+-----------------+-----------------+-----------------+
| Treatment days, | 128.8           | 133.2           | 136.1           |
| mean            |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

*[Reviewer comment:]{.underline}*

*Drug exposure appears to be adequate to allow for assessment of safety,
given limitations with the design and duration of this study, and
recognizing that compliance reporting is commonly unreliable. Compliance
assessment was based on data from the Diskus dose counter, which cannot
accurately assess whether patients actually received the drug that was
dispensed.*

##### Adverse events

Adverse events (AEs) were common in this study. These data are
summarized in Table 11.1.25. A small dose response effect was noted for
all AEs with FP 500 and FP 250. AEs occurred in 80% of FP 500-treated
patients, 76% of FP 250-treated patients, and in 74% of placebo-treated
patients. AEs occurring more frequently with FP 500 and FP 250 than with
placebo included upper respiratory tract infection, headaches,
candidiasis of the mouth or throat, throat irritation, musculoskeletal
pain, viral respiratory infection, upper respiratory inflammation, nasal
congestion/blockage, hoarseness/dysphonia, and sinusitis, among others.
A dose response effect was noted for candidiasis of the mouth or throat,
viral respiratory infections, and upper respiratory inflammation with FP
500 and FP 250 \[clinstat\\copd\\flta3025.pdf, pages 802-820\].

*[Reviewer comment:]{.underline}*

*It remains unexplained why there were many more patients in FP 250 and
FP 500 than in placebo who reported upper and lower respiratory tract
AE's that could be construed as "COPD exacerbations" (URTI, viral RTI,
upper respiratory inflammation, among others see below), yet these did
not seem to be reflected in the secondary efficacy endpoint of "COPD
exacerbations."*

Many of the AEs noted are noted in the labels for Flovent MDI and
Flovent Rotadisk. These include upper respiratory tract infection,
headaches, candidiasis, viral respiratory infections, nasal congestion,
dysphonia, sinusitis, diarrhea, and rhinitis. AEs reported in this study
that are not noted in current labeling for other Flovent products
include musculoskeletal pain, edema and swelling, nausea and vomiting,
dyspepsia, airway irritation (throat irritation, cough, rhinorrhea), and
neurologic AEs (sleep disorder, dizziness, anxiety, malaise and fatigue)
\[clinstat\\copd\\flta3025.pdf, pages 802-820\].

**Table 11.1.25. Adverse events more frequent than placebo and occurring
**3%, FLTA3025 \[clinstat\\copd\\flta3025.pdf, pages 802-820\].

+------------------------+--------------+--------------+--------------+
| **Adverse event**      | **Placebo**  | **FP 250**   | **FP 500**   |
|                        |              |              |              |
|                        | **N = 206**  | **N = 216**  | **N = 218**  |
|                        |              |              |              |
|                        | **n (%)**    | **n (%)**    | **n (%)**    |
+========================+==============+==============+==============+
| All adverse events\*   | 152 (74)     | 165 (76)     | 174 (80)     |
+------------------------+--------------+--------------+--------------+
| Upper respiratory      | 41 (20)      | 45 (21)      | 45 (21)      |
| tract infection        |              |              |              |
+------------------------+--------------+--------------+--------------+
| Headaches              | 19 (9)       | 30 (14)      | 30 (14)      |
+------------------------+--------------+--------------+--------------+
| Candidiasis            | 1 (\<1)      | 12 (6)       | 29 (13)      |
| mouth/throat           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Throat irritation      | 9 (4)        | 25 (12)      | 25 (11)      |
+------------------------+--------------+--------------+--------------+
| Musculoskeletal pain   | 19 (9)       | 27 (13)      | 22 (10)      |
+------------------------+--------------+--------------+--------------+
| Viral respiratory      | 11 (5)       | 12 (6)       | 19 (9)       |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Upper respiratory      | 11 (5)       | 14 (6)       | 15 (7)       |
| inflammation           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Nasal                  | 8 (4)        | 16 (7)       | 13 (6)       |
| congestion/blockage    |              |              |              |
+------------------------+--------------+--------------+--------------+
| Hoarseness/dysphonia   | 2 (1)        | 13 (6)       | 10 (5)       |
+------------------------+--------------+--------------+--------------+
| Sinusitis\*\*          | 6 (3)        | 12 (6)       | 10 (5)       |
+------------------------+--------------+--------------+--------------+
| Cough                  | 9 (4)        | 17 (8)       | 9 (4)        |
+------------------------+--------------+--------------+--------------+
| Fever                  | 6 (3)        | 7 (3)        | 9 (4)        |
+------------------------+--------------+--------------+--------------+
| Diarrhea               | 7 (3)        | 8 (4)        | 8 (4)        |
+------------------------+--------------+--------------+--------------+
| Chest symptoms         | 8 (4)        | 4 (2)        | 8 (4)        |
+------------------------+--------------+--------------+--------------+
| Muscle pain            | 3 (1)        | 3 (1)        | 8 (4)        |
+------------------------+--------------+--------------+--------------+
| Nausea and vomiting    | 1 (\<1)      | 8 (4)        | 7 (3)        |
+------------------------+--------------+--------------+--------------+
| Malaise and fatigue    | 2 (1)        | 7 (3)        | 7 (3)        |
+------------------------+--------------+--------------+--------------+
| COPD                   | 5 (2)        | 5 (2)        | 6 (3)        |
+------------------------+--------------+--------------+--------------+
| Sleep disorders        | 2 (1)        | 8 (4)        | 5 (2)        |
+------------------------+--------------+--------------+--------------+
| Rhinorrhea/post nasal  | 5 (2)        | 7 (3)        | 5 (2)        |
| drip                   |              |              |              |
+------------------------+--------------+--------------+--------------+
| Rhinitis               | 4 (2)        | 7 (3)        | 4 (2)        |
+------------------------+--------------+--------------+--------------+
| Edema and swelling     | 4 (2)        | 7 (3)        | 4 (2)        |
+------------------------+--------------+--------------+--------------+
| Dyspeptic symptoms     | 4 (2)        | 6 (3)        | 4 (2)        |
+------------------------+--------------+--------------+--------------+
| Dizziness              | 2 (1)        | 6 (3)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Anxiety                | 3 (1)        | 6 (3)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+

\*AEs with dose response effect are highlighted

\*\*Composed of AEs for sinusitis and sinusitis/sinus infection

The highest incidence of AEs was in the first month of treatment (42%
placebo, 43% FP 250, 46% FP 500). Throat irritation and
dysphonia/hoarseness were most prevalent early in the study
\[clinstat\\copd\\flta3025.pdf, page 131\]. The most common-drug related
AEs included candidiasis of the mouth or throat, throat irritation,
hoarseness/dysphonia, and headaches \[clinstat\\copd\\flta3025.pdf, page
132\].

A listing of AEs of low frequency that have been associated with use of
corticosteroids, such as infection, GI bleeding, diabetes and glucose
intolerance, is found in Table 11.1.26.

Small numbers of these AEs were observed without a strong association
with FP 250 or FP 500 \[clinstat\\copd\\flta3025.pdf, pages 802-820\].

*[Reviewer comment:]{.underline}*

*Other than the few patients reported as having "skin hemorrhage," there
were no patients who were reported as having bruising or purpura. One
would expect a fairly significant number of patients to have had this
AE, given the large doses of FP used and given the older ages of the
patients studied. Unfortunately this study was not designed to
specifically look for cataract or systemic bone effects, both known to
be associated with systemic effects of corticosteroids. Ophthalmologic
examination and studies to assess osteoporosis would have been helpful
to address these concerns, although the 6-month duration of this study
would have been inadequate to fully assess the bone, ocular, endocrine
(diabetes, adrenal suppression), and cardiovascular (hypertension)
consequences of chronic high-dose ICS.*

Table 11.1.26. Selected adverse events of low frequency, FLTA3025
\[clinstat\\copd\\flta3025.pdf, pages 802-820\].

+------------------------+--------------+--------------+--------------+
| **Adverse event**      | **Placebo**  | **FP 250**   | **FP 500**   |
|                        |              |              |              |
|                        | **N = 206**  | **N = 216**  | **N = 218**  |
|                        |              |              |              |
|                        | **n (%)**    | **n (%)**    | **n (%)**    |
+========================+==============+==============+==============+
| All adverse events\*   | 152 (74)     | 165 (76)     | 174 (80)     |
+------------------------+--------------+--------------+--------------+
| Fungal                 | 0 (0)        | 0 (0)        | 1 (\<1)      |
| gastrointestinal       |              |              |              |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Gastrointestinal       | 0 (0)        | 1 (\<1)      | 0 (0)        |
| hemorrhage             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Gastrointestinal       | 1 (\<1)      | 0 (0)        | 0 (0)        |
| ulcers                 |              |              |              |
+------------------------+--------------+--------------+--------------+
| Pneumonia              | 3 (1)        | 3 (1)        | 4 (2)        |
+------------------------+--------------+--------------+--------------+
| Muscle atrophy,        | 0 (0)        | 2 (\<1)      | 0 (0)        |
| weakness               |              |              |              |
+------------------------+--------------+--------------+--------------+
| Candidiasis,           | 1 (\<1)      | 2 (\<1)      | 2 (1)        |
| unspecified site       |              |              |              |
+------------------------+--------------+--------------+--------------+
| Fractures              | 5 (2)        | 2 (\<1)      | 3 (1)        |
+------------------------+--------------+--------------+--------------+
| Skin hemorrhage        | 0 (0)        | 1 (\<1)      | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Hypertension           | 2 (\<1)      | 3 (1)        | 4 (2)        |
+------------------------+--------------+--------------+--------------+
| Increased blood        | 1 (\<1)      | 0 (0)        | 1 (\<1)      |
| pressure               |              |              |              |
+------------------------+--------------+--------------+--------------+
| Hyperglycemia          | 1 (\<1)      | 2 (\<1)      | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Diabetes mellitus      | 0 (0)        | 0 (0)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Impaired glucose       | 0 (0)        | 0 (0)        | 1 (\<1)      |
| tolerance              |              |              |              |
+------------------------+--------------+--------------+--------------+
| Cataracts              | 0 (0)        | 0 (0)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Ocular pressure        | 1 (\<1)      | 0 (0)        | 0 (0)        |
| disorders              |              |              |              |
+------------------------+--------------+--------------+--------------+

Subgroup analysis of AEs by gender, age, and race will be reviewed in
the Integrated Review of Safety section of this document.

##### Deaths and serious adverse events

There were no deaths reported during the study. One placebo-treated
patient, #38176, died after completing the study. She was a 72-year old
woman who presented to the emergency room 17 days after her final study
visits with abdominal pain and was found to have ovarian adenocarcinoma.
She died eight days later \[clinstat\\copd\\flta3025.pdf, page 134\].

Serious adverse events (SAEs) occurred in treatment groups at similar
frequencies (placebo 6%, FP 250 7%, FP 500 7%). The most common SAEs
were COPD exacerbation and pneumonia, which occurred at similar
frequencies in placebo-treated, FP 250-treated, and FP 500-treated
patients \[clinstat\\copd\\flta3025.pdf, pages 825-827\].

SAEs due to fractures occurred only in FP-treated patients. There were
no SAEs due to fractures in placebo-treated patients. There were two
patients with fractures in the FP 250 group. Patient #36401, was a
70-year old white male, who fractured the left ulna, and sustained a
compression fracture of the thoracic spine and a lumbar vertebral
fracture after falling from a ladder. Patient #36172, was a 63-year old
white male who developed a spinal fracture after falling from a ladder.
There was one FP 500-treated patient who had a SAE due to a fracture. He
was patient #37809, a 50-year old male who developed a fracture to the
neck after an automobile accident \[clinstat\\copd\\flta3025.pdf, pages
202, 204, 225, 3557, 3558, 3569\].

Other SAEs occurred less commonly and had comparable frequencies in the
treatment groups.

*[Reviewer comment:]{.underline}*

*It is interesting that SAEs due to fractures occurred only in
FP-treated patients. It is possible that this may represent a hint of a
safety signal, however, there was associated trauma in each of these
events, and there was only a small number of SAEs due to fractures
reported. Also, any patient with pre-existing osteoporosis or
pathological fractures was specifically excluded from this study, and a
rapid progression from asymptomatic to pathological fracture seems very
unlikely. AEs and SAEs should be followed closely for similar
occurrences during future trials of longer duration.*

##### Withdrawals due to adverse events

Patients withdrew due to AEs at slightly higher rates in the FP
500-treated group (10%, 22/218) than in the FP 250-treated group (6%,
6/216), or the placebo-treated group (6%, 13/206). The most common AE
that led to withdrawal from the study was exacerbation of COPD (FP 500
2%, FP 250, 2%, placebo 2%). Although there were small numbers of
patients with withdrawals due to AEs, only FP-treated patients and no
placebo-treated patients had withdrawals for pneumonia or pneumonitis,
upper respiratory tract infection, throat irritation,
hoarseness/dysphonia, and fractures \[clinstat\\copd\\flta3025.pdf,
pages 828-830\]. Other than COPD exacerbation, there were no more than 3
patients in any treatment group for any individual AE leading to
withdrawal.

*[Reviewer comment:]{.underline}*

*Throat irritation and hoarseness/dysphonia are recognized to be
associated with the use of inhaled corticosteroids.
Pneumonia/pneumonitis and fracture may be represent a safety signal, as
these the occurrence of these withdrawals exclusively in FP-treated
patients, and these have been associated with the use of systemic
corticosteroids.*

##### Vital signs

There were no clinically significant changes from baseline in median
values of vital signs for any of the treatment groups
\[clinstat\\copd\\flta3025.pdf, pages 147, 903-905\]. Patient #38574 was
a 71-year old black male who was treated with FP-250 who had an episode
of dizziness associated with hypotension, bradycardia, tingling of the
fingers, and shortness of breath. This episode resolved without
treatment \[clinstat\\copd\\flta3025.pdf, page 3252\].

##### Physical examination

Physical examinations were performed at Screening and at the Week 24
visit or the Discontinuation visit. Data were recorded on subject
progress notes, but not on case report forms (CRFs). Physical
examination abnormalities were recorded as AEs on the CRFs, but no
summary of physical examinations was provided \[NDA 20-833, SE1-004, BM,
9/17/01, page 3\]. Evidence of skin bruising would have been useful to
record.

##### Oropharyngeal examination

Oropharyngeal examinations were performed at screening, at each
treatment visit, and at the Discontinuation visit
\[clinstat\\copd\\flta3025.pdf, page 59\]. Data was recorded on subject
progress notes, but not on case report forms (CRFs). Oropharyngeal
examination abnormalities were recorded as AEs on the CRFs, but no
summary of oropharyngeal examinations was provided \[NDA 20-833,
SE1-004, BM, 9/17/01, page 2\].

##### Laboratory studies

Small numbers of patients had shifts in % lymphocyte, % neutrophils, and
WBC counts from baseline at Weeks 12 and 24 and Discontinuation.

There was a greater percentage of patients with shifts in % lymphocytes
to low in patients treated with FP 500 (7%, 11/165) and FP 250 (4%,
6/161), than placebo (0%, 0/151) at week 12. This observation was also
present at week 24 for FP 500 (3%, 4/143), FP 250 (5%, 7/135), and
placebo (4%, 5/124), and at discontinuation for FP 500 (16%, 9/56), FP
250 (12%, 8/66), and placebo (9%, 6/70) \[clinstat\\copd\\flta3025.pdf,
pages 831-840\].

There was a greater percentage of patients treated with FP 500 (5%,
9/165) and FP 250 (6%, 10/161) with shifts in % neutrophils to high than
placebo (1%, 2/151) at week 12. The percentage of patients with shifts
in % neutrophils to high was similar at week 24 for FP 500 (3%, 4/143),
FP 250 (4%, 5/135), and placebo (2%, 3/124). There was a greater
percentage of FP 500 (23%, 13/56) and FP 250 (17%, 11/66) with shifts in
% neutrophils to high at discontinuation than for placebo (9%, 6/70)
\[clinstat\\copd\\flta3025.pdf, pages 831-840\].

There was a greater percentage of patients with shifts in WBC count to
high in patients treated with FP 500 (5%, 8/165) and FP 250 (5%, 8/161),
than for placebo (\<1%, 1/151) at week 12. Shifts in WBC count to high
were present at week 24 for patients treated with FP 500 (3%, 5/143), FP
250 (8%, 11/135), and placebo. Shifts in WBC counts to high were also
noted at discontinuation for patients treated with FP 500 (23%, 13/56),
FP 250 (17%, 11/66), and placebo (9%, 6/70)
\[clinstat\\copd\\flta3025.pdf, pages 831-840\].

*[Reviewer comment:]{.underline}*

*The shifts in % lymphocytes, % neutrophils, and WBC counts in
FP-treated patients at week 12 could be systemic corticosteroid effects
of inhaled FP. The differences between FP and placebo groups are absent
or smaller at week 24. It is unclear why the differences between FP and
placebo groups are less pronounced at week 24 if they are related to
systemic effects of FP. It is possible that the less prominent
difference between treatment groups could be due to tolerance of this
effect, or due to dropouts. It is possible that the difference the
treatment groups is not related to FP, however. The high percentage of
patients with shifts in % lymphocytes, % neutrophils, and WBC counts at
discontinuation are likely to be in patients discontinuing from COPD
exacerbations who received treatment with systemic corticosteroids. It
should be noted that there was a slightly higher rate of viral
respiratory infection and sinusitis in FP-treated patients. These AEs
could be also be manifestations of immunologic effects (i.e.,
lymphopenia and impaired neutrophil function) of inhaled FP.*

An increase from baseline in ALT was noted in a higher percentage of
patients treated with FP 500 (5%, 8/157) than with FP 250 (0%, 0/160) or
placebo (\<1%, 1/150) at week 12. An increase from baseline in ALT was
noted in a higher percentage of patients treated with FP 500 (6%, 9/146)
than with FP 250 (\<1%, 1/137) or placebo (\<1%, 1/124) at week 24.
Increases from baseline in ALT at discontinuation were noted in similar
percentages of patients for FP 500 (2%, 1/56), FP 250 (3%, 2/66), and
placebo (4%. 3/71) \[clinstat\\copd\\flta3025.pdf, pages 842-850\].

Increases from baseline were noted for AST and alkaline phosphatase in a
small percentage of patients treated with FP 500, FP 250, and placebo.
The percentage with increases was slightly greater for FP 500 and FP 250
than for placebo at week 12 and week 24, but not at discontinuation
\[clinstat\\copd\\flta3025.pdf, pages 842-850\].

*[Reviewer comment:]{.underline}*

*The higher percentage of patients in the FP groups with increases in
ALT, AST, and alkaline phosphatase may be related to the hepatic
metabolism of FP. FP is a Cyp3A4 substrate, and the liver would clear
any systemically absorbed drug. Differences between treatment groups
were less prominent at Week 24. Increases in LFTs are not noted in
current labeling for other FP products, although drug interaction with
3A4 inhibitors has recently been added. It should be noted that there
was only one AE reported for increased liver function tests, patient
#36375, a 49-year old white female treated with FP-500. This patient had
mildly elevated ALT and AST values at baseline
\[clinstat\\copd\\flta3025.pdf, page 140\]*.

There was a greater percentage of patients who had increases from
baseline in glucose at week 12 for FP 500 (8%, 14/167) and FP 250 (9%,
15/160) than with placebo (5%, 8/149). There was no meaningful
difference in the percentage of patients who had increases from baseline
in glucose at week 24 between FP 500 (5%, 8/146), FP 250 (2%, 3/137),
and placebo (6%, 7/123). There was no meaningful difference in the
percentage of patients who had increases from baseline in glucose at
discontinuation for FP 500 (9%, 5/56), FP 250 (5%, 3/66), and placebo
(7%, 5/69) \[clinstat\\copd\\flta3025.pdf, pages 842-850\]. It should be
noted that the sponsor defined an exceptionally liberal definition for
high glucose, \>175 mg/ml. It is likely that this liberal definition of
high glucose would result in a lower sensitivity of detecting a
difference between treatment groups \[clinstat\\copd\\flta3025.pdf, page
3598\].

*[Reviewer comment:]{.underline}*

*Hyperglycemia is an effect of systemic corticosteroids. Although there
are higher percentages of FP 500 and FP 250 patients with increases in
glucose at Week 12 than placebo patients, there is no meaningful
difference between treatment groups at week 24 and at discontinuation.
The significance of this finding is unclear, although it is interesting
to speculate that it may be due to lack of compliance with a therapy
that has no perceived benefit to the patient (see CDRQ). This may
represent a tolerance to a drug-related systemic effect. There were no
meaningful differences between treatment groups in the frequency of the
small number of AEs due to diabetes mellitus, hyperglycemia, or impaired
glucose tolerance This observation is much less reassuring because of
the sponsor's exceptionally liberal definition of elevated blood
glucose.*

There were few patients with hematology or chemistry results outside of
values specified as normal by the sponsor. The few patients with results
outside of the range specified as normal by the sponsor were evenly
distributed between treatment groups \[clinstat\\copd\\flta3025.pdf,
pages 851-872\]. Patients with notable abnormal laboratory values are
noted below.

Patient #36933, a 70-year old white male who was treated with FP 250,
discontinued due to hyperglycemia \[crf\\flta3025\\6234\\p0036933.pdf\].
Patient \# 37434, a 60-year old white male treated with FP 500,
developed uncontrolled diabetes mellitus that resolved after 77 days. He
did not withdraw from the study \[clinstat\\copd\\flta3025.pdf, pages
140, 3376\]. Patient #36375, was a 49-year old white female treated with
FP-500 who had mildly elevated values for ALT (238 U/L) and AST (134
U/L) at baseline that remained elevated throughout the study
\[clinstat\\copd\\flta3025.pdf, page 140\].

##### ECGs

There were a few clinically significant changes in ECGs from baseline
for each of the treatment groups in the study. Patients with clinically
significant changes in ECGs are summarized in Table 11.1.27. There was
no significant difference between treatment groups in the number or
character of the changes in ECGs.

Table 11.1.27. Patients with clinically significant changes in ECGs from
baseline, FLTA3025 \[clinstat\\copd\\flta3025.pdf, pages 141-146\].

+-------------+-------------+-------------+---------------------------+
| **Patient   | **          | **Time of   | **ECG abnormality**       |
| number**    | Treatment** | ab          |                           |
|             |             | normality** |                           |
+=============+=============+=============+===========================+
| 36879       | Placebo     | Disc        | Recent anteroseptal MI,   |
|             |             | ontinuation | anterolateral ischemia    |
+-------------+-------------+-------------+---------------------------+
| 36971       | Placebo     | Weeks 12,   | Atrial flutter            |
|             |             | 24          |                           |
+-------------+-------------+-------------+---------------------------+
| 38176       | Placebo     | Week 12     | Sinus tachycardia,        |
|             |             |             | ischemic ST depression    |
+-------------+-------------+-------------+---------------------------+
| 38232       | Placebo     | Disc        | Atrial flutter            |
|             |             | ontinuation |                           |
+-------------+-------------+-------------+---------------------------+
| 36978       | FP 250      | Week 12     | Prolonged QT interval     |
|             |             |             |                           |
|             |             | Week 24     | Ischemic changes, RBBB    |
+-------------+-------------+-------------+---------------------------+
| 37034       | FP 250      | Week 12     | Non-specific STT changes  |
|             |             |             |                           |
|             |             | Week 12     | Infero-apical ischemia,   |
|             |             | repeat      | STT changes               |
|             |             |             |                           |
|             |             | Week 24     | New inferior MI           |
+-------------+-------------+-------------+---------------------------+
| 37371       | FP 250      | Disc        | Atrial flutter            |
|             |             | ontinuation |                           |
+-------------+-------------+-------------+---------------------------+
| 37837       | FP 250      | Week 12     | Old MI, increase in ST    |
|             |             |             | depression                |
+-------------+-------------+-------------+---------------------------+
| 38079       | FP 500      | Week 24     | Possible new MI, repeat   |
|             |             |             | ECG was normal            |
+-------------+-------------+-------------+---------------------------+
| 38573       | FP 500      | Week 24     | New onset atrial          |
|             |             |             | fibrillation/flutter      |
+-------------+-------------+-------------+---------------------------+
| 38736       | FP 500      | Week 24     | Atrial fibrillation       |
+-------------+-------------+-------------+---------------------------+
| 38746       | FP 500      | Week 24     | Evolving anterolateral    |
|             |             |             | ischemic changes          |
+-------------+-------------+-------------+---------------------------+

Median QTc intervals by both Bazette and Fridericia formulae were
similar for each of the treatment groups. The incidence of QT, QTcB, and
QTcF intervals ≥440 msec was similar for each of the treatment groups.
There were eight patients with changes in QTc greater than 470 msec. One
was treated with placebo, three were treated with FP 250, and four were
treated with FP 500. These patients are summarized in Table 11.1.28.

Table 11.1.28. Patients with QTcB intervals \>470 msec post-screening,
FLTA3025 \[clinstat\\copd\\flta3025.pdf, page 146\]

+-------------+-------------+-------------+-------------+-------------+
| **Patient   | **          | **Screening | **Week 12   | **Week 24   |
| number**    | Treatment** | QTcB,**     | QTcB,**     | or DC QTcB, |
|             |             |             |             | msec**      |
|             |             | **msec**    | **msec**    |             |
+=============+=============+=============+=============+=============+
| 36284       | Placebo     | 436         | 458         | 482         |
+-------------+-------------+-------------+-------------+-------------+
| 37494       | FP 250      | 413         | 428         | 484         |
+-------------+-------------+-------------+-------------+-------------+
| 38030       | FP 250      | 452         | 472         | 472         |
+-------------+-------------+-------------+-------------+-------------+
| 38482       | FP 250      | 426         | 416         | 498         |
+-------------+-------------+-------------+-------------+-------------+
| 35934       | FP 500      | 475         | 473         | 491         |
+-------------+-------------+-------------+-------------+-------------+
| 37984       | FP 500      | 468         | \--         | 479         |
+-------------+-------------+-------------+-------------+-------------+
| 38276       | FP 500      | 438         | 472         | 450         |
+-------------+-------------+-------------+-------------+-------------+
| 38748       | FP 500      | 414         | 420         | 500         |
+-------------+-------------+-------------+-------------+-------------+

*[Reviewer comment:]{.underline}*

*Although there was a slightly higher incidence of patients with QTcB
\>470 post-screening in the FP 250 and FP 500 groups than the placebo
group, these findings were present in only small number of patients and
could be a chance occurrence.*

### References

1.  Position Statement, American Thoracic Society: Standards for the
    Diagnosis and Car of Patients with Chronic Obstructive Pulmonary
    Disease. Am J Respir Crit Care Med 1995;152:S77-S120.

2.  Anthonisen NR, Wright EC, et al. Bronchodilator Response in Chronic
    Obstructive Pulmonary Disease. Am Rev Respir Dis 1986;133: 814-819.

3.  Barnes PJ. Chronic Obstructive Pulmonary Disease. New Engl J Med
    2000;343:269-280.

4.  Eliasson, O and Degraff AC. The Use of Criteria for Reversibility
    and Obstruction to Define patient Groups for Bronchodilator Trials.
    Am Rev Respir Di*s* 1985;132:858-864.

5.  Anthonisen NR et al. Antibiotic Therapy in Exacerbations of Chronic
    Obstructive Pulmonary Disease. Ann Int Med 1987;106:196-204.

6.  Snow V, et al. The Evidence Base for Management of Acute
    Exacerbations of COPD: ACCP-ASIM Clinical Practice Guideline,
    Part 1. Chest 2001;119;1185-1189.

7.  McCrory DC, et al . Management of Acute Exacerbations of COPD: A
    Summary and Appraisal of Published Evidence. Chest
    2001;119:1190-1209.

8.  The Lung Health Study Research Group. Effect of Inhaled
    Triamcinolone on the Decline in Pulmonary Function in Chronic
    Obstructive Pulmonary Disease. New Engl J Med 2000;343:1902-1909.

9.  National Asthma Education and Prevention Program. Expert Panel
    Report 2: Guidelines for the Diagnosis and Management of Asthma.
    National Institutes of Health Publication Number 97-4051. Bethesda,
    MD, 1997.

10. Petty TL. The national mucolytic study: Results of a randomized,
    double-blind, placebo-controlled study of iodinated glycerol in
    chronic obstructive bronchitis. Chest 1990;97:75-83.

11. Rubin BK, Ramirez O, Ohar JA. Iodinated glycerol has no effect on
    pulmonary function, symptom score, or sputum properties in patients
    with stable chronic bronchitis. Chest 1996;109:348-352.

12. Mahler DA, Weinberg DH, et. al. The measurement of dyspnea.
    Contents, interobserver agreement, and physiologic correlates of two
    new clinical indexes. Chest 1984;97:751-758.

13. Guyatt GH, Berman LB, Townsend M, et. al. A measure of quality of
    life for clinical trials in chronic lung diseases. Thorax
    1987;42:773-778.

## SFCA3006: A randomized, double-blind, parallel-group trial of evaluating the safety and efficacy of the Diskus formulations of Salmeterol 50 mcg BID and fluticasone propionate 500 mcg BID individually and in combination as compared to placebo in COPD subjects

> Study initiated: 9/24/98
>
> Study completed: 5/5/00
>
> Study report dated: 3/22/01

\[clinstat\\copd\\sfca3006.pdf, page 1\]

### Summary and reviewer\'s conclusion of study results

This was a randomized, double-blind, placebo-controlled, parallel group,
multicenter, 24-week trial designed to evaluate the efficacy and safety
of salmeterol xinafoate (SAL) 50 mcg BID, fluticasone propionate FP 500
mcg BID, the combination of SAL 50 mcg /FP 500 mcg BID, and placebo in
patients with chronic obstructive pulmonary disease (COPD).

As in Study FLTA3025, the proportion of patients with reversibility
enrolled in this study is much higher than is found in the population of
COPD patients at large^1-4^. Of all study patients, there were 54% of
patients who were considered to be "reversible" (≥12% and ≥200 mL
increase in FEV~1~ with bronchodilator). In addition, the degree of
reversibility for the reversible population was high---29.8%. The mean
degree of reversibility in the 46% of the patients who comprised the
"non-reversible" population, 8.8%, was similar to the mean reversibility
described in studies of COPD patients as a whole^1-4^. Therefore, there
are serious concerns as to whether the patient population studied in
this clinical trial is representative of the COPD population as a
whole^1-4^, as broadly stated in the labeling for the proposed
indication. This is a critical deficiency of this study. Non-Caucasian
patients, who make up a substantial proportion of the COPD
population^1,3^, were also under-represented in this study.

The primary efficacy endpoint was the mean change in FEV~1~ from
Baseline to study endpoint. The primary efficacy endpoint supports the
efficacy of FP 500 compared to placebo in this population. The mean
change from baseline in FEV~1~ for the FP 500 group at endpoint was 109
mL, 113 mL more than the placebo group at endpoint. This comparison was
statistically significant at p \<0.001. This change corresponds to an
effect size of 9.6%.

Small decreases in the Chronic Bronchitis Symptom Questionnaire (CBSQ)
were noted for all active treatment groups at Weeks 3 to 24 and at
endpoint. In general, decreases were numerically superior to the placebo
group, which also showed an improvement in score. Decreases in the CBSQ
were not clinically significantly different from the placebo group for
any of the active treatment groups at any time, however. The differences
between the Transition Dyspnea Indices (TDIs) for FP 500 and placebo
were not greater than the minimal clinically significant TDI of 1.0
point at Endpoint. Week-by-week analysis failed to show significance at
any of the 10 interim measurements from Weeks 1 to 24, except for Week
24. Neither the CBSQ nor the TDI provide support for the efficacy of FP
in COPD.

The incidence of COPD exacerbations was similar for all treatment
groups. First COPD exacerbations, first moderate to severe COPD
exacerbations, study withdrawals, and withdrawals due to COPD
exacerbation were similar in the FP 500 and placebo groups. First COPD
exacerbations, first moderate to severe COPD exacerbations, study
withdrawals, and withdrawals due to COPD exacerbation were similar in
the SAL 50 and SAL 50/FP 500 groups, which were less frequent than in
the placebo group. A non-standard definition of COPD exacerbation was
used that would have favored the finding of efficacy of FP in a COPD
population with a high degree of reversibility. As a general statement,
incidence or severity of COPD exacerbations did not provide support for
the efficacy of FP in COPD.

A small mean increase from baseline in AM PEFR was noted in the FP 500
(12.9 L/min) and SAL 50 (16.8 L/min) groups at the end of the study. A
larger mean increase was observed in the SAL 50/FP 500 group (31.9
L/min). Overall, the FP 500, SAL 50, and SAL 50/FP 500 groups had small
decreases in the number of puffs of Ventolin used per day, in the number
of awakenings per night, and had small increases in the percent of
nights with no awakenings requiring Ventolin use. Increases in the
overall Chronic Respiratory Disease Questionnaire (CDRQ) score for FP
500 and SAL 50/FP 500 were less than the specified clinically
significant difference from the change in baseline in the placebo group,
and provide no support for efficacy. This is an important negative
finding, since one of the stated objectives of this study was to compare
the health-related quality of life (QOL) in COPD patients receiving
active treatment compared to placebo over this 24-week study.

The sponsor performed a subgroup analysis of efficacy by smoking status.
In general, larger effects for primary and secondary efficacy endpoints
were noted in patients who stopped smoking prior to the conduct of the
study.

The sponsor performed a subgroup analysis of efficacy for non-reversible
patients. This subgroup analysis demonstrated numerically greater
changes in FEV~1~ from baseline at study endpoint for all active
treatments compared with placebo. Similar results were also noted for
most secondary endpoints. The difference from placebo for mean change
from baseline at endpoint for the reversible group for FP 500 was 124
mL. This was 23% greater than the difference from placebo for mean
change from baseline at endpoint for the non-reversible group, which for
FP 500 was 101 mL.

There was a suggestion of a systemic corticosteroid effect in some
patients in the FP 500 and SAL 50/FP 500 groups for post-cosyntropin
stimulation change \<5.6 mcg/dL. The larger decrease in mean
post-cosyntropin stimulation cortisol levels from Day 1 to Endpoint for
FP 500 and SAL 50/FP 500 is suggestive of a systemic effect, as was the
smaller increase in mean cortisol levels in the FP 500 and SAL 50/FP 500
groups at Endpoint.

Duration of exposure was inadequate to fully assess safety, since the
short efficacy endpoints in this study fail to address the safety
consequences of long-term (\> 6 months) use of high-dose, high-potency
inhaled corticosteroids, particularly with regard to bone,
dermatological, and ocular adverse events, as well as the potential for
HPA axis recovery. AEs occurred in 80% of FP 500-treated patients, 78%
of SAL 50/FP 500-treated patients, and in 69% of placebo-treated
patients. AEs occurring more frequently with FP 500 and SAL 50/FP 500
than with placebo included headaches, upper respiratory tract infection,
throat irritation, upper respiratory inflammation, viral respiratory
infection, candidiasis of the mouth or throat, nasal
congestion/blockage, and muscle cramps and spasms. There were three
deaths in this study, all in the placebo group. The percentage of
patients was SAEs during the treatment phase were similar among the
treatment groups, with the highest in the FP 500 group (7%, 12/173),
followed by placebo (6%, 11/185), and SAL 50/FP 500 (5%, 9/169). Vital
signs and ECGs showed no clinically significant differences between
treatment groups.

In summary, based on the primary endpoint, efficacy was demonstrated for
the FP 500 group in this study. An open issue is whether the study
population adequately reflects the overall population of US COPD
patients, although both the reversible and the non-reversible subgroups
showed some change from baseline on this endpoint. Subgroup analysis
demonstrated a numerically greater effect size for the reversible
compared to the non-reversible population, although the difference was
not as marked as in FLTA3025. Efficacy measurements that supported FP
500 included FEV~1~, PEFR, and measures of bronchodilator use. COPD
exacerbations did not support the efficacy of FP 500. The health-related
quality of life instrument (CRDQ), the Transitional Dyspnea Index (TDI),
and the Chronic Bronchitis Symptoms Questionnaire (CBSQ) provided no
support for the efficacy of FP 500. Data for the safety endpoints chosen
for this study are generally inadequate to make a determination of the
long-term safety of FP in the population studied because the study was
of insufficient duration for known systemic corticosteroid effects such
as osteoporosis, cataracts, hypertension, diabetes, or skin changes such
as easy bruisability or skin thinning to become apparent. It should be
noted that the study was not designed to specifically assess these AEs,
and patients with prior pathological fracture, osteoporosis, significant
hypertension or diabetes, cataracts, or glaucoma were specifically
excluded. Although not specifically addressed in this document (see
review by Dr. L. Gilbert-McClain), the safety issue of long-term
systemic corticosteroid effects will be similar for SAL 50/FP 500
(Advair^®^) in this population.

### Study design

This was a randomized, double-blind, placebo-controlled, parallel group,
multicenter trial of 24-weeks duration. Approximately 600 patients were
to be randomized at approximately 55 study centers. A total of 691
patients were enrolled at 64 study sites \[clinstat\\copdsfca3006.pdf,
pages 45, 11,818\].

### Objectives

This study had three objectives \[clinstat\\copd\\sfca3006.pdf, pages
44, 11822\]. They were:

1.  To compare the efficacy of SAL 50 mcg BID, FP 500 mcg BID, the
    combination of SAL 50 mcg /FP 500 mcg BID, and placebo when
    administered by the Diskus over a 24-week treatment period in the
    treatment of COPD patients

2.  To compare the safety of SAL 50 mcg BID, FP 500 mcg BID, the
    combination of SAL 50 mcg /FP 500 mcg BID, and placebo when
    administered by the Diskus over a 24-week treatment period in the
    treatment of COPD patients

3.  To compare quality of life (QOL) in COPD patients receiving SAL 50
    mcg BID, FP 500 mcg BID, the combination of SAL 50 mcg/FP 500 mcg
    BID, and placebo when administered by the Diskus over a 24-week
    treatment period

### Inclusion criteria

Inclusion criteria for this study are listed below. These reflect
protocol amendments. \[clinstat\\copd\\sfca3006.pdf, pages
11824-11826\]:

1.  Age ≥40 years

2.  Male or female gender

-   A female was eligible to enter and participate if she was of
    non-childbearing potential or was of child-bearing potential with a
    negative serum pregnancy test at screening and an acceptable method
    of contraception

3.  Established history of COPD in accordance with the American Thoracic
    Society (ATS) definition^1^:

-   Abnormal tests of expiratory flow that do not change markedly over
    periods of several months

```{=html}
<!-- -->
```
-   Airflow obstruction may be structural or functional

```{=html}
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```
-   Bronchial hyperreactivity may be present as measured by improvement
    after inhalation of a beta-adrenergic agent or worsening after
    inhalation of methacholine or histamine

```{=html}
<!-- -->
```
-   Emphysema and chronic bronchitis are incorporated into COPD, and any
    individual may have one or both of these conditions

4.  A history of cough productive of sputum on most days for at least 3
    months of the year, for at least 2 years, that is not attributed to
    another disease process. Patients must have a score of ≥4 on the
    Chronic Bronchitis Symptom Questionnaire (CBSQ) at Treatment Day 1

5.  Current or prior history of at least 20 pack-years of cigarette
    smoking. If the patient is an ex-smoker, smoking must have been
    discontinued for at least 6 months prior to screening. Current
    smokers were counseled regarding the hazards of continuing to smoke
    and the benefits of discontinuation. Patient who decided to stop
    smoking at the Screening Visit were not eligible for participation
    in the study. Patients making a conscious decision to stop smoking
    at anytime during the study and who refrain from smoking for \>4
    weeks were to be discontinued from the study. Patients who start
    smoking during the study and smoke for at least 7 consecutive days
    were to be discontinued from the study.

6.  Severity

-   Baseline FEV~1~ \<65% or predicted but \>0.70 L, or FEV~1~ \<0.70 L
    and \>40% but still \<65% of the predicted normal value (Crapo), and

```{=html}
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```
-   FEV~1~/FVC ratio of ≤70% at screening

7.  A score if ≥2 in the Modified Medical Research Council Dyspnea Scale
    at screening:

Modified Medical Research Council Dyspnea
Scale\[clinstat\\copd\\sfca3006.pdf, page 11876\]

  ----------- ---------------------------------------------------------------
  **Grade**   **Description**

  0           Not troubled with breathlessness except with strenuous exercise

  1           Troubled by shortness of breath when hurrying on the level or
              walking up a slight hill

  2           Walks slower than people of the same age on the level because
              of breathlessness or has to stop for breath when walking at own
              pace on the level

  3           Stops to breathe after walking about 100 yards or after a few
              minutes on the level

  4           Too breathless to leave the house or breathless when dressing
              or undressing
  ----------- ---------------------------------------------------------------

8.  Has not received systemic corticosteroid and/or high-dose inhaled
    corticosteroid therapy for at least 6 weeks prior to the Screening
    Visit. High dose inhaled corticosteroids are defined as:

-   Beclomethasone dipropionate ≥1008 mcg/day

-   Triamcinolone acetonide ≥1600 mcg/day

-   Flunisolide ≥2000 mcg/day

-   Fluticasone propionate MDI ≥880 mcg/day

-   Fluticasone propionate Diskus ≥1000 mcg/day

-   Budesonide ≥1600 mcg/day

9.  Able to tolerate a 2-week run-in period during which the following
    medications were discontinued:

-   Inhaled corticosteroids

-   Ipratropium

-   Nedocromil sodium and cromolyn sodium

-   Anti-leukotriene agents

-   Intranasal steroids

-   Any beta-agonist other than Ventolin

-   Theophylline, unless at a stable dosage for one month

10. Able to complete a diary card and subject questionnaires

11. Able to effectively use the Diskus and MDI inhalers, spirometry
    equipment, and mini-Wright peak flow meter

12. Provide a signed, dated, and witnessed informed consent

*[Reviewer comment:]{.underline}*

*The sponsor's paraphrase of the ATS definition of COPD places an
emphasis on reversibility. While reversible obstruction does occur in
the COPD population, it should not be considered central to the
definition. The process underlying COPD is one of progressive loss of
lung tissue, leading primarily to structural obstruction as opposed to
functional^1^. The ATS definition follows:*

> *"COPD is defined 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."^1^*

*The inclusion criteria allow for patients who were receiving fairly
large doses of inhaled corticosteroids prior to enrollment. This may
have the effect of enriching the study for patients who were responsive
to inhaled corticosteroids, as one would expect patients with no
response or a poor response to have their treatment discontinued.*

### Exclusion criteria

Exclusion criteria for this study are listed below. These reflect
protocol amendments. \[clinstat\\copd\\sfca3006.pdf, pages
11826-11830\]:

1.  Current diagnosis of asthma in accordance with the ATS definition:

-   Increased responsiveness of the tracheobronchial tree

-   Paroxysms of dyspnea, wheezing, and cough, which may vary from mild
    and almost undetectable to severe and unremitting

-   Primary physiological manifestation of hyperresponsiveness is
    variable airway obstruction

-   Variability may be manifest in improvements of obstruction following
    bronchodilators or corticosteroids or increased obstruction caused
    by drugs or other stimuli

2.  Requirement for any of the following medications:

-   Beta-blockers

-   Digitalis

-   Ketoconazole, fluconazole

-   Monoamine oxidase inhibitors

-   Tricyclic antidepressants

-   Phenothiazines

-   Immunosuppressive agents including cyclosporine, methotrexate, and
    gold

-   Use of inhaled short-acting bronchodilator within 6 hours prior to
    screening

-   Use of any short acting form of oral beta-agonist, short-acting form
    of theophylline or other bronchodilator within 12 hours prior to
    screening

-   Use of any twice daily form of an inhaled or oral beta-agonist or
    controlled-release form of theophylline within 48 hours of screening

3.  Requirement for pulmonary rehabilitation that is initiated during
    the study. Participation in a maintenance pulmonary rehabilitation
    program was allowed.

4.  A respiratory disorder other than COPD (e.g., lung cancer,
    bronchiectasis, sarcoidosis, tuberculosis, lung fibrosis); history
    of lobectomy within one year of the screening visit. Patients with
    alpha-1-antitrypsin deficiency were excluded.

5.  Requirement for a continuous positive pressure device for COPD or
    sleep apnea.

6.  Any significant concurrent diseases that would place the subject at
    risk, interfere with clinical evaluations, or influence study
    participation, including but not limited to:

-   History of symptomatic or clinically significant pathologic
    fractures

-   Clinically significant cardiac disease

-   Systemic arterial hypertension if the subject is poorly compliant
    with medications, likely to require frequent changes in medication
    during the study period, or requires therapy with beta-blockers

```{=html}
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```
-   Hepatic disease

-   Renal disease requiring dialysis or at risk of requiring dialysis
    within 6 months of screening

-   Neurologic disease

-   Uncontrolled hyperthyroidism or hypothyroidism

-   Diabetes mellitus that is either poorly controlled or complicated by
    significant renal or cardiovascular disease

-   Severe hematologic disease

-   Active peptic ulcer

-   Disorders of humoral or cellular immunity

-   Cushing's disease

-   Addison's disease

-   Presence of glaucoma requiring treatment with non-selective
    beta-blockers

-   History of malignancy except for localized basal cell or squamous
    cell carcinoma of the skin that has been resected and patients
    curatively treated and disease free for at least 2 years may be
    considered for entry after discussion with the Glaxo Wellcome
    medical advisor

-   Inadequately controlled psychiatric illness

-   Mental retardation

-   Peripheral vascular disease

-   Use of a pacemaker

7.  Requirement for supplemental oxygen with the following exceptions:

-   Lives at an altitude above 3000 feet and does not require more than
    2 L of oxygen per minute for more than 12 hours per day

-   Does not require more than 2 L of oxygen per minute for more than 2
    hours per day for exertion

8.  A known or suspected hypersensitivity to inhaled corticosteroids,
    beta-agonists or lactose. Gastrointestinal lactose intolerance is
    not an exclusion criterion.

9.  A known or suspected history of alcohol or drug abuse within the
    previous two years

10. 12-lead ECG at screening is abnormal and clinically significant

11. A patient has clinically significant abnormalities found on 24-hour
    Holter monitoring (at selected sites)

12. A moderate or severe exacerbation of COPD during the run-in period

13. Chest X-ray reveals clinically significant abnormalities not
    believed to be due to the presence of COPD

14. Received an investigational drug within 30 days prior to entry into
    the run-in period

15. A participating investigator, sub-investigator, study coordinator,
    or employee of a participating investigator, or an immediate family
    member of the aforementioned

16. An abnormal and clinically significant laboratory test a the
    screening visit which is still abnormal on repeat analysis

17. Previous participation in a fluticasone and/or salmeterol study via
    the Diskus for COPD

*[Reviewer comment:]{.underline}*

*The sponsor uses an ATS definition of asthma from 1987. This definition
makes no reference to the role of inflammation in asthma. A more
appropriate definition might be the National Asthma Education and
Prevention Program (NAEPP) definition of asthma, which refers to
inflammation as well as reversible airway obstruction^5^. Taken
strictly, this exclusion criterion would exclude all patients who have
reversible airway obstruction, and such patients were not excluded in
this study.*

### Protocol amendments

There were four protocol amendments, dated 9/4/98, 12/17/98, 2/11/00,
and 6/23/00 \[clinstat\\copd\\sfca.pdf, page 11932\]. A substudy
protocol for genotyping during the study was also added on 9/9/98
\[clinstat\\copd\\sfca.pdf, page 11937\]. This substudy will not be
reviewed.

Originally, the protocol called for approximately 600 patients to be
randomized at approximately 55 study centers. The protocol was amended
on 2/11/00 to allow for approximately 700 patients to be randomized at
approximately 65 study centers \[clinstat\\copd\\sfca3006.pdf, pages
11930\]. Urinalyses were not performed and were removed in Protocol
Amendment 1 \[clinstat\\copd\\sfca3006.pdf, page11919\]. The protocol
was amended to provide subgroup analyses of patients who had an increase
in percent of predicted FEV~1~ less than 10% after albuterol at the
screening visit, of former smokers, and of current smokers
\[clinstat\\copd\\sfca3006.pdf, pages 12009-12010\].

The FEV~1~/FVC ratio required for entry into the study was changed from
≤65% to ≤70% in Protocol Amendment 2 \[clinstat\\copd\\sfca3006.pdf,
page 11923\].

*[Reviewer comment:]{.underline}*

*The effect of the change in the FEV~1~/FVC ratio would be to allow
entry of patients with both those with milder obstruction (who would be
perhaps more likely to have reversibility) and those with very severe
obstruction with accompanying air trapping. This amendment was made
after the study had been started. The inclusion criteria specifying the
FEV~1~ and the level of dyspnea will minimize any impact of this change.
Other protocol amendments otherwise included minor changes to wording
and study design that had little impact on the evaluation of efficacy or
safety.*

### Study procedures

Study procedures are displayed in Table 11.2.1. Patients provided an
informed consent, and received a medical history and physical
examination at the screening visit. Chest X-ray, pregnancy test,
screening labs, and ECGs were performed. Twenty-four hour Holter
monitoring was performed at selected sites. Spirometry with assessment
of reversibility was also performed. Reversibility was assess by
performing spirometry 30 minutes after patient self-administration of 4
puffs of Ventolin MDI without a spacer or holding chamber
\[clinstat\\copd\\sfca3006.pdf, page 11837\].

There was a two-week, single-blind, run-in period for patients meeting
entrance criteria. Patients had all prohibited concurrent medication
discontinued and were given Ventolin MDI or nebules to be used as needed
for duration of the trial, including the run-in. Patients received
placebo via the Diskus BID during the run-in, and baseline observations
were made for morning peak expiratory flow rates (PEFR), Ventolin use,
and night-time awakenings that required Ventolin use
\[clinstat\\copd\\sfca3006.pdf, pages 11836-11837\]. The purpose of the
single-blind run-in period was to establish baseline pulmonary function
and diary card data for at least 10 of the 14 days. Patient compliance
with medication and recording of diary data was also assessed
\[clinstat\\copd\\flta3025.pdf, page 11837\]. Patient were to record
daily morning PEFRs, nighttime awakenings requiring Ventolin use, use of
rescue Ventolin, and any medical problems experienced
\[clinstat\\copd\\sfca3006.pdf, page 11837\].

Criteria for patients to be eligible for randomization included the
following \[clinstat\\copd\\sfca3006.pdf, pages 11837-11838\]:

-   Satisfaction of inclusion and exclusion criteria

-   At least 70% compliant with study medication during the run-in

-   Completed diary data for at least 10 of the 14 days of the run-in

-   Had not started or stopped smoking during the run-in

-   Proficiency in use of the peak flow meter

-   Able to safely withhold prohibited study medications

-   Had not experienced a moderate or severe COPD exacerbation

Patients who completed the run-in period and met all randomization
criteria were assigned to one of four double-blind treatments via the
Diskus for 24 weeks \[clinstat\\copd\\sfca3006.pdf, page 11830\]:

-   FP 500 mcg BID via Diskus (1 inhalation BID)

-   Salmeterol (SAL) 50 mcg BID via Diskus (1 inhalation BID)

-   Salmeterol (SAL) 50 mcg/FP 500 mcg via Diskus (1 inhalation BID)

-   Placebo via Diskus BID

Assignment to study drug was to be stratified according to the patients'
response to reversibility testing with Ventolin at screening to a
non-reversible group and a reversible group. Non-reversible patients
were defined as having an absolute volume increase \<200 mL or an
absolute volume increase of ≥200 mL with baseline FEV~1~ reversibility
of \<12%. Reversible patients were defined as having an absolute volume
increase ≥200 mL with baseline FEV~1~ reversibility of ≥12%
\[clinstat\\copd\\sfca3006.pdf, page 11832\].

*[Reviewer comment:]{.underline}*

*The definition of reversibility is critical for this study. In
addition, the proportion of patients with reversible obstruction is also
critical, even if the proportion in each of the four treatment groups is
similar. FP and SAL are effective for treatment of asthma, and inclusion
of a high proportion of patients with a significant degree of
reversibility would be likely to result in an overstatement of efficacy
for the entire group. Although assignment to study drug was stratified
according to reversibility based on the above definition, no analysis
was planned or provided for these subgroups. Instead, the sponsor
provided a subgroup analysis that was based on a different definition.
This issue and its effects are discussed in Section 11.2.16.1 of this
document, "Data sets analyzed".*

Patients were evaluated weekly for the first four weeks of treatment,
every two weeks until week 8, and then every four weeks for the
remainder of the study. Patients who developed an exacerbation could be
treated with antibiotic therapy as an outpatient for two exacerbations,
but were discontinued from the study if a third exacerbation occurred.
Subjects with exacerbations requiring treatment with systemic
corticosteroids were to be discontinued from the study
\[clinstat\\copd\\scfa3006.pdf, page 11823\].

Patient evaluations at each of the clinic visits included spirometry.
Symptoms were also evaluated with the Baseline/Transition Dyspnea Index
(BDI/TDI), Chronic Bronchitis Symptom Questionnaire (CBSQ), and
assessment of the severity of any COPD exacerbations since the last
evaluations. Health outcomes were assessed with the Chronic Respiratory
Disease Questionnaire (CRDQ), a health-related quality of life
instrument \[clinstat\\copd\\sfca3006.pdf, page 11874\]. The BDI/TDI,
CBSQ, and CRDQ instruments and the instrument for assessment of COPD
exacerbations are described below in Section 1.2.12, Assessment of signs
and symptoms. Cosyntropin stimulation testing, 12-hour serial FEV~1~,
and 24-hour Holter monitoring were performed at selected sites .

Patients completed diary cards during the treatment period. Patients
measured PEFRs in triplicate prior to the morning dose of study
medication. The highest of 3 PEFR values was recorded on diary card.
Patients also were to record nighttime awakenings requiring Ventolin
use, the use of supplemental Ventolin, any medical problems, any need
for other concomitant medication, and AEs
\[clinstat\\copd\\sfca3006.pdf, pages 11842-11843\].

Table 11.2.1. Study outline, SFCA3006 \[clinstat\\copd\\sfca3006.pdf,
page 11873\].

<table>
<colgroup>
<col style="width: 19%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td><strong>Screen</strong></td>
<td><strong>Run-in</strong></td>
<td colspan="11"><strong>Double-blind treatment period</strong></td>
<td><strong>DC</strong></td>
</tr>
<tr class="even">
<td><strong>Visit number</strong></td>
<td></td>
<td></td>
<td><strong>1</strong></td>
<td><strong>2</strong></td>
<td><strong>3</strong></td>
<td><strong>4</strong></td>
<td><strong>5</strong></td>
<td><strong>6</strong></td>
<td><strong>7</strong></td>
<td><strong>8</strong></td>
<td><strong>9</strong></td>
<td><strong>10</strong></td>
<td><strong>11</strong></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Treatment Day/Week</strong></td>
<td></td>
<td><p><strong>Day</strong></p>
<p><strong>–14 to 1</strong></p></td>
<td><strong>Day 1</strong></td>
<td><strong>Wk 1</strong></td>
<td><strong>Wk 2</strong></td>
<td><strong>Wk 3</strong></td>
<td><strong>Wk 4</strong></td>
<td><strong>Wk 6</strong></td>
<td><strong>Wk8</strong></td>
<td><strong>Wk 12</strong></td>
<td><strong>Wk 16</strong></td>
<td><strong>Wk 20</strong></td>
<td><strong>Wk 24</strong></td>
<td></td>
</tr>
<tr class="even">
<td>Informed consent</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Medical history</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Smoking cessation counseling</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Chest X-ray</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Physical examination</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Pregnancy test</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Reversibility test</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Review inhalation technique</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Medical Research Council Questionnaire</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Clinical laboratory tests</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>24-hr Holter monitoring*</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>12-lead ECG and rhythm strip</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Vital signs</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Cosyntropin stimulation testing*</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Oropharyngeal exam</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Review smoking status</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>AE detection</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Spirometry testing</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>12-hr serial FEV<sub>1</sub>*</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Exacerbation assessment</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Dispense/review diary card</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Chronic bronchitis symptom questionnaire</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>BDI/TDI dyspnea scale</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Quality of life questionnaire</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Dispense PEFR devices and Ventolin MDI/nebules</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Dispense study medication</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Concurrent medication assessment</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Discharge from study</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
</tbody>
</table>

\*Selected sites

### Allowable concurrent medications

Allowable concurrent medications included
\[clinstat\\copd\\sfca3006.pdf, page 11833\]:

-   Inhaled Ventolin MDI and/or nebules, provided by the sponsor for use
    as relief medication. Ventolin was to be withheld for at least 6
    hours prior to each treatment visit.

-   Antibiotics were permitted for treatment of two exacerbations.
    Patients were dropped from the study if a third COPD exacerbation
    occurred.

-   Antidepressants other than MAO inhibitors and tricyclic
    antidepressants

-   Theophylline, if on a stable dose for at least one month prior to
    screening

### Prohibited medications

The following medications were prohibited
\[clinstat\\copd\\scfa3006.pdf, page 11833-11834\]:

-   Corticosteroids other than the study medication

-   Beta-agonists other than the Ventolin supplied by the sponsor

-   Concurrent use of any other prescription or over-the-counter
    medication which may affect the course of COPD or interact with
    study medications. These medications were to be discontinued at
    least 2 weeks prior to randomization.

### Drug product and placebo

The sponsor provided the following study treatments
\[clinstat\\copd\\sfca3006.pdf, pages 55-56\]:

-   Placebo Diskus, for the single-blind run-in period and 24-week
    treatment period

-   FP Diskus 500 mcg, 1 puff BID for the 24-week double-blind study
    period

-   SAL Diskus 50 mcg, 1 puff BID for the 24-week double-blind study
    period

-   SAL 50 mcg/FP Diskus 500 mcg, 1 puff BID for the 24-week
    double-blind study period

-   Market-image Ventolin MDI and nebules for each subject as rescue
    medication

-   Cortrosyn 0.25 mg injection for cosyntropin stimulation testing at
    selected sites

*[Reviewer comment:]{.underline}*

*The FP Diskus 500 mcg is not an approved product. The sponsor has
argued dose proportionality of the approved 250 mcg and proposed 500 mcg
products in another study included in this submission. The
interpretation of these dose proportionality data is a review issue
discussed elsewhere in this review, and discussed in depth in the
clinical pharmacology review.*

The batch numbers of medication were used in this study are displayed in
Table 11.2.2.

Table 11.2.2. Batch numbers of study medication, SFCA3006
\[clinstat\\copd\\scfa3006.pdf, page 56\].

+-----------------------------------+-----------------------------------+
| **Product**                       | **Batch numbers**                 |
+===================================+===================================+
| Placebo Diskus                    | WP25L4                            |
|                                   |                                   |
|                                   | WP31R9                            |
|                                   |                                   |
|                                   | WP2GHW                            |
+-----------------------------------+-----------------------------------+
| FP Diskus 500 mcg                 | U98/024C                          |
+-----------------------------------+-----------------------------------+
| SAL Diskus 50 mcg                 | WP2D8B                            |
|                                   |                                   |
|                                   | WP2NLT                            |
|                                   |                                   |
|                                   | WP2T35                            |
+-----------------------------------+-----------------------------------+
| SAL Diskus 50 mcg/FP Diskus 500   | U97/061C                          |
| mcg                               |                                   |
|                                   | WP2NPB                            |
|                                   |                                   |
|                                   | B003371                           |
+-----------------------------------+-----------------------------------+
| Ventolin MDI, 90 mcg/puff         | 8ZP0909                           |
|                                   |                                   |
|                                   | 9ZP0259                           |
+-----------------------------------+-----------------------------------+
| Ventolin nebules, 0.098%, 2.5     | 980905                            |
| mg/3 mL                           |                                   |
|                                   | 990903                            |
|                                   |                                   |
|                                   | 980901                            |
+-----------------------------------+-----------------------------------+
| Cortrosyn 0.25 mg injection       | 2240697731                        |
|                                   |                                   |
|                                   | 2300199731                        |
|                                   |                                   |
|                                   | 2310299731                        |
+-----------------------------------+-----------------------------------+

The sponsor states that the formulations of Flovent used in this study
were representative of the commercial product in terms of input
materials, scale of manufacture, manufacturing equipment, and
manufacturing process. The only difference between the batches of
Flovent that were supplied for this study and the commercial product was
the device coloration. All batches of Ventolin nebules and Ventolin MDI
used in this study were the approved commercial product. The placebo
used in this study was identical to the active product used in this
study except for the absence of active drug \[NDA 20-833, SE1-004,
9/17/01, page 3\].

### Assessment of compliance

Patient compliance with the drug dosing schedule was determined from the
dose counter on the Diskus devices. Patients who were less than 70%
compliant with the use of study medication during the 2-week run-in were
not eligible to be randomized into the study
\[clinstat\\copd\\scfa3006.pdf, pages 58, 81\].

### Assessment of signs and symptoms

Patient COPD symptoms were evaluated with the Chronic Bronchitis Symptom
Questionnaire (CBSQ), Baseline/Transition Dyspnea Index (BDI/TDI), and
assessment of the severity of any COPD exacerbations since the last
evaluations. These instruments are described below.

The CBSQ was composed of selected questions from the Petty Subject
Evaluation Questionnaire^6^ and the Revised Global Petty Questionnaire
for Ease of Cough and Sputum Clearance^7^ The CBSQ evaluated cough
frequency and severity, sputum release, and chest discomfort on a 0 to
4, 5-point scale. Individual scores were summed to provide a Global
Assessment Score (GAS). As noted in the inclusion criteria, patients
must have had a GAS of ≥4 at Treatment Day 1 to qualify for the study
\[clinstat\\copd\\sfca3006.pdf, page 49\].

Additional data describing the CBSQ were included with the application.
These data describe the administration of the CBSQ. The patient was
allowed to read each question along with the interviewer and verbally
select the response that best described the status of that particular
symptom on a typical day during the past week. After reading the
question, as written, with the subject, the interviewer used discussion
questions and observations to assist the subject in providing as precise
an answer as possible \[clinstat\\other\\cbsqvalidationdocument.pdf,
page 6\]. A Minimally Clinically Important Change (MCIC) for the CBSQ
was determined to be a change from baseline of 1.4 in the GAS
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 11\]. The
calculation of the MCIC assessed the change in GAS for individual
subjects by collecting them into one of four categories to assess a
Global Rating of Change (GRC)
\[clinstat\\other\\cbsqvalidationdocument.pdf, pages 8-9\]:

1.  GRC = 0, ±1: No change in symptoms of chronic bronchitis

2.  GRC = ±2, ±3: A minimal change in symptoms of chronic bronchitis

3.  GRC = ±4, ±5: A moderate change in symptoms of chronic bronchitis

4.  GRC = ±6, ±7: A large change in symptoms of chronic bronchitis

However the validation package indicates that there was poor correlation
between the GAS and the GRC used to calculate the MCIC. Pearson and
Spearman's correlation coefficients between GAS and GRC were only from
0.25 to 0.34 \[clinstat\\other\\cbsqvalidationdocument.pdf, page 9\].
Furthermore, large standard deviations in the GRC and MCIC were noted.
The standard deviations were large enough for each of the GRC categories
to substantially overlap each other
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 11\].

*[Reviewer comment:]{.underline}*

*The CBSQ was administered in such a fashion that the interviewer might
have influenced patient responses. The poor correlation between the GAS
and GRC and the large standard deviation in the GRC indicate that the
MCIC is not likely to be valid. This instrument will not be able to
provide support for the efficacy of FP.*

The BDI/TDI was used to provide a clinical measurement of baseline and
change in dyspnea. The degree of functional impairment at baseline due
to dyspnea, the magnitude of task to provoke dyspnea, and the magnitude
of effort that provoked dyspnea were rated on a 0 to 4, 5-point scale to
derive the BDI. Changes from baseline in functional impairment,
magnitude of task, and magnitude of effort were assessed at each
subsequent visit with a -3 to +3, seven-point scale, the TDI
\[clinstat\\copd\\sfca3006.pdf, pages 62-67\].

The sponsor provided a reference for this instrument that showed a weak
correlation of the BDI with FEV~1~, FVC, and the 12-minute walk distance
with correlation coefficients of 0.41, 0.56, and 0.60^8^. TDI correlated
only weakly with change in the change in the 12-minute walk distance,
with a correlation coefficient of 0.33. There was no correlation of TDI
with change in FEV~1~ or change in FVC. Although not noted in this
study, the sponsor had noted in FLTA3025 that they considered a change
from BDI to TDI of 1.0 to be clinically relevant
\[clinstat\\copd\\flta3025.pdf, page 67, Correspondence submitted to IND
50,703, Meeting request package, 2/6/98\]. The sponsor did not include a
validation package with this application or with the meeting request
package of 2/6/98.

*[Reviewer comment:]{.underline}*

*Degree of functional impairment, magnitude of task, and magnitude of
effort are likely to be highly correlated variables, in this reviewer's
opinion, and therefore will inflate any observed positive or negative
treatment effect. This instrument will not be likely to provide support
for the efficacy of FP because of this deficiency and because of the
lack of validation.*

The investigator assessed the severity of any COPD exacerbations at each
clinic visit using a three-level scale, mild to severe. Mild
exacerbations were defined as use of more than 12 puffs or 4 nebules of
relief bronchodilator per day for more than 2 consecutive days, but
without the need for additional medication. Moderate exacerbations were
defined as requiring either antibiotics or corticosteroids. Severe
exacerbations were defined as requiring inpatient admission for
treatment \[clinstat\\copd\\sfca3006.pdf, page 68\].

*[Reviewer comment:]{.underline}*

*This is not the standard definition of COPD exacerbation. In fact, this
definition describes situations that reflect a worsening of airway
bronchoconstriction. This definition of exacerbation would be likely to
favor the finding of efficacy of FP in patients who have a high degree
of reversibility. The most widely accepted definition of COPD
exacerbation follows^9^:*

-   *Type 1 = All of the following symptoms*

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```
-   *Increased dyspnea, increased sputum volume, increased sputum
    purulence*

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```
-   *Type 2 = Two of the following symptoms*

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```
-   *Increased dyspnea, increased sputum volume, increased sputum
    purulence*

```{=html}
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```
-   *Type 3 = One of the following symptoms*

```{=html}
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```
-   *Increased dyspnea, increased sputum volume, increased sputum
    purulence and one of the following:*

```{=html}
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```
-   *URI within 5 days, fever without non-respiratory cause, increased
    wheezing, increased coughing, increase in respiratory rate of heart
    rate ≥20%*

Patients were to complete diary records during the treatment period each
morning. Patients recorded the highest of three PEFRs measurements
performed each morning prior the dose of study medication, the number of
inhalations of supplemental Ventolin use over the preceding 24 hours,
and the number of nighttime awakenings requiring the use of Ventolin
during the preceding night \[clinstat\\copd\\sfca3006.pdf, pages
68-69\].

### Health-related quality of life instrument

Health outcomes were assessed with the Chronic Respiratory Disease
Questionnaire (CRDQ), a health-related quality of life instrument^10^
\[clinstat\\copd\\sfca3006.pdf, page 69\]. It is worth noting that
comparative quality of life (QOL) was one of the three primary
objectives that the sponsor identified as important outcomes of the
study. The sponsor states that the instrument is an
interviewer-administered, disease-specific, validated questionnaire
designed to measure the impact of chronic respiratory disease and its
treatments on the patient's COPD-related quality of life. The CRDQ is a
20-item questionnaire that evaluates health-related quality of life
across four domains---dyspnea, fatigue, emotional function, and mastery
over the disease. The responses for each of the 20 items were summed to
provide an overall assessment of health-related quality of life. A
physical score was calculated based on the sum of scores of the dyspnea
and fatigue domains and an emotional score was calculated based on the
sum of the scores of the emotional function and mastery domains. The
CRDQ was completed at Day 1, and Weeks 2, 4, 8, 24, and Discontinuation.

### Efficacy variables 

Efficacy variables for this study are described below.

#### Primary efficacy variable

The primary efficacy variables for this study was the pre-dose FEV~1~
and the 2-hour post dose FEV~1~ collected at Day 1, and Weeks 1, 2, 3,
4, 6, 8, 12, 16, 20, and 24 \[clinstat\\copd\\sfca3006.pdf, page
11853\].

For primary efficacy measures, treatments were compared as follows
\[clinstat\\copd\\sfca3006.pdf, page 11853\].

-   SAL 50/FP 500 to SAL 50: Pre-dose FEV~1~, to evaluate the
    contribution of FP 500 to the combination product

-   SAL 50/FP 500 to FP 500: Two-hour post dose FEV~1~, to evaluate the
    contribution of SAL 50 to the combination product

-   SAL 50 to placebo: Two-hour post-dose FEV~1~, to evaluate the
    efficacy of the individual component

-   FP 500 to placebo: Pre-dose FEV~1~, to evaluate the efficacy of the
    individual component

*[Reviewer comment:]{.underline}*

*Only the pre-dose FEV~1~ is relevant to the assessment of efficacy for
FP 500 relevant to placebo, therefore this comparison will be the focus
of the review. Other active treatment arms will only be discussed only
if relevant to the efficacy and/or safety assessment of FP 500.*

The baseline FEV~1~ was the pre-dose FEV~1~ at treatment Day 1. The
primary analyses compared endpoint and baseline measurements for the
primary efficacy variables. The endpoint was defined in the protocol as
the final evaluable measurement for the patient. For patients who
discontinued from the study the endpoint was the last evaluable
measurement taken prior to withdrawal \[clinstat\\copd\\sfca3006.pdf,
page 11853\]. Therefore, the FEV~1~ at the Discontinuation Visit was not
used for any efficacy analysis.

*[Reviewer comment:]{.underline}*

*As this review is concerned with the efficacy of FP in the treatment of
COPD, only pre-dose FEV~1~ measurements will be examined. Two-hour
post-dose FEV~1~ measurements were performed by the sponsor to help
assess the efficacy of SAL 50 and the contribution of SAL to the
efficacy of the combination SAL 50/FP 500 product.*

*In FLTA3025, the sponsor stated that their rationale for not using the
FEV1 at the Discontinuation Visit was that patients might have stopped
taking study drug prior to the visit and might have been taking another
drug that could affect results \[clinstat\\copd\\flta3025.pdf, page
66\]. Although it is not stated in this study, it is likely the sponsor
had the same rationale in this study. The sponsor's plan to carry the
last measurement from the preceding visit forward for discontinuing
patients also affects the interpretation of efficacy results, however.*

Treatment groups were compared using ANCOVA F-tests with baseline as the
covariate. All inferential analyses were performed on the mean change
from Baseline. Ninety-five percent confidence intervals were provided
for treatment differences in the mean changes from Baseline
\[clinstat\\copd\\sfca3006.pdf, pages 11853, 81-82\].

#### Secondary efficacy variables

Secondary efficacy variables included change from baseline in the global
and individual domains of the CBSQ, the BDI/TDI score at each of the
treatment visits, number and percent of exacerbations of COPD, time to
first COPD exacerbation, number of withdrawals and time to withdrawals.
Morning PEFR, daily use of Ventolin, percentage of nights with no
awakenings requiring Ventolin, frequency of nighttime awakenings
requiring Ventolin, and percent of days without using Ventolin were also
summarized. The sponsor performed 12-hour serial spirometry at Day 1 and
Week 12 in a subset of patients at selected sites to demonstrate that
SAL 50- and SAL 50/FP 500-induced increases were sustained for 12 hours
\[clinstat\\copd\\sfca3006.pdf, pages 113, 11854\].

Summary statistics were provided for all secondary endpoints. Changes
from baseline in the Global Assessment Score (GAS) of the CBSQ were
compared between treatment groups using an ANCOVA F-test with treatment
group, investigator, and baseline value as covariates. Overall and
pairwise treatment comparisons of the BDI/TDI scores were performed by
ANOVA F-test. Time to first COPD exacerbation, number of withdrawals,
and time to withdrawals were analyzed using survival analysis
\[clinstat\\copd\\sfca3006.pdf, pages 11854-11855\].

The CRDQ was also used to compare changes in the COPD-related quality of
life for treatment groups as measured by an overall score and for each
of the four domains. An improvement of at least 10 in overall score was
considered to be an overall improvement in COPD specific quality of
life. At each visit, treatment group comparisons were made comparing the
change from baseline using ANCOVA, controlling for baseline and
investigator. A difference between treatment groups in mean change from
baseline was considered clinically meaningful the difference was
statistically significant and had a minimum of ≥0.5 point improvement
per question per item \[clinstat\\copd\\scfa3006.pdf, pages
11855-11866\].

### Safety variables

Safety variables for this study included AEs, ECGs, hematology and
clinical chemistry studies, oropharyngeal examinations, and vital signs
\[clinstat\\copd\\sfca3006.pdf, pages 11844-11849\]. Summary statistics
were to be provided for each of the safety endpoints
\[clinstat\\copd\\sfca3006.pdf, pages 11857-11858\].

*[Reviewer comment:]{.underline}*

*Although the safety variables that were chosen are appropriate to
assess the local and systemic safety of FP, it would have been
preferable to also have formal ophthalmologic examinations and
assessments of bone density, although given the duration of the study,
it is unclear whether such tests would be sufficiently sensitive to
detect a change.*

Cosyntropin (Cortrosyn®) stimulation testing was performed at selected
study sites on Day 1 and Week 24 or Discontinuation
\[clinstat\\copd\\sfca3006.pdf, pages 11857-11858\]. The sponsor
performed the short cosyntropin stimulation test according to the
cosyntropin package insert. Blood samples were to be drawn 30-60 minutes
after administration of cosyntropin \[clinstat\\copd\\sfca3006.pdf, page
11849\]. Threshold values of 14.5 mcg/dL and 5.6 mcg/dL were used in the
analysis because a HPLC assay was used. The sponsor states that a less
specific radioimmunoassay was used for the higher reference values given
in the cosyntropin package insert \[clinstat\\copd\\sfca3006.pdf, page
90\].

Twenty-four hour Holter monitoring was to be conducted at approximately
14 study centers on approximately 160 patients. Baseline monitoring was
performed during the run-in period. Post-treatment monitoring was to be
performed at Week 4. Monitoring was to start approximately 1 our prior
to administration of the morning dose of study medication and continued
for 24 hours \[clinstat\\copd\\sfca3006.pdf, page 11845-11847\].

### Statistical considerations

Imputation of missing data was planned for the primary efficacy
parameter and the humanistic outcomes. Last observation carried forward
analysis was to be performed. \[clinstat\\copd\\sfca3006.pdf, page
11852\].

#### Data sets analyzed

The primary population for the analysis of both efficacy and safety was
the intent-to-treat population, defined as all randomized subjects who
received at least one dose of study drug \[clinstat\\copd\\sfca3006.pdf,
pages 11851-11852\].

Originally, the sponsor did not plan any subgroup analyses
\[clinstat\\copd\\sfca3006.pdf, page 11852\]. In Protocol Amendment 3
(2/11/00), the sponsor added a subgroup analysis for patients who have
an increase in percent predicted FEV~1~ of less than 10% after albuterol
at the screening visit. This group was called the
"poorly-reversible-percent of predicted patients"
\[clinstat\\copd\\sfca3006.pdf, page 11931\]. Subgroup analyses of
former smokers and current smokers were added in Protocol Amendment 4
(6/23/00) \[clinstat\\copd\\sfca3006.pdf, page 11935\].

*[Reviewer comment:]{.underline}*

*This analysis was to be provided to support the approval of the product
outside the US. \[clinstat\\copd\\sfca3006.pdf, page 107\]. The sponsor
indicates that this definition reflects current opinion of the European
Respiratory Society \[NDA 20-833, SE1-004, pages 1-2, 8/10/01\].*

*As in FLTA3025 and as noted earlier in this document, assignment to
study drug was to be stratified according to the patients' response to
reversibility testing with bronchodilator at screening to non-reversible
and reversible patients. The non-reversible group was defined earlier in
the protocol as patients with an absolute volume increase of \<200 mL or
absolute volume increase ≥200 mL with baseline reversibility assessment
of \<12% , and is based on the ATS definition of reversibility
\[clinstat\\copd\\sfca3006.pdf, page 11832; NDA 20-833, SE1-004, pages
1-2, 8/10/01\]. As noted earlier, subgroup analysis initially was not
provided for these either the non-reversible or reversible groups. The
proportion of patients with reversibility will be critical to determine
if the population studied accurately reflects the population of patients
with COPD.*

*The sponsor provided an extensive subgroup analysis of the
"poorly-reversible population." As noted above, the poorly-reversible
population" was defined as those patients who had an increase in percent
predicted FEV~1~ of less than 10% after albuterol at the screening
visit. Although this may be the accepted definition for the ERS, it is a
curious way of expressing reversibility, as it uses a theoretical value
as the baseline (percent predicted FEV~1~), rather than an actually
measured value, such as FEV~1~ at baseline. The ERS definition and the
subgroup analysis of the poorly reversible population are not relevant
to approval of this drug for this indication in the US, however, and
this subgroup analysis will receive only brief review.*

#### Statistical power

The sponsor calculated that a sample size of 145 patients per treatment
arm would be necessary to provide \>85% power to detect a clinically
meaningful significant difference of 0.1 liter between treatment groups.
The sponsor assumed a standard deviation for the change from baseline
FEV~1~ of 0.28 liters, and a level of significance of 0.05, using a
two-sample t-test \[clinstat\\copd\\sfca3006.pdf, page 11851\].

The sponsor amended the protocol in Protocol Amendment 3 to allow for
randomization of 700 patients with a total of 175 patients per treatment
arm \[clinstat\\copd\\sfca3006.pdf, page 11930\]. The sponsor increased
the planned sample size to account for any data which required exclusion
from the primary efficacy analysis, such as an investigator not meeting
study standards or subjects that have a baseline FEV~1~ assessment
without a subsequent FEV~1~ assessment \[clinstat\\copd\\sfca3006.pdf,
page 11930\].

### Results

The sponsor excluded data from patients enrolled at the site of
Investigator #\[ \] from population and efficacy analyses as a result of
a quality assurance assessment. The sponsor indicates that there was
reason to doubt the integrity of the data from patients enrolled at this
site. Data for these patients were included in the analyses of safety
\[clinstat\\copd\\sfca3006.pdf, page 92\]. Investigator #\[ \] was Dr.
\[ \], who was at study Site #\[ \]
\[clinstat\\other\\listofinvestigators.pdf, page 8\]. Dr. \[ \] enrolled
\[ \] patients in the study \[clinstat\\copd\\sfca3006.pdf, page 2235\].

The sponsor received a letter from Investigator #\[ \]stating that the
data generated from this study might be unreliable. The sponsor
performed an impact analysis to determine if the removal of the data
submitted by this investigator would change interpretation of the data.
The impact analysis showed that there would be no change in the
interpretation of the data, and included data from this investigator in
the study report \[clinstat\\copd\\sfca3006.pdf, page 92\]. Investigator
#\[ \] was Dr. \[ \], who was at Site #\[ \]
\[clinstat\\other\\listofinvestigators.pdf, page 9\]. Dr. \[ \] enrolled
\[ \] patients in the study \[clinstat\\copd\\sfca3006.pdf, page
2263-2264\].

*[Reviewer comment:]{.underline}*

*This reviewer compared results for the primary efficacy endpoint from
the impact analysis with the data including Investigator #\[ \] in the
analysis. There was essentially no difference in the change from
baseline in FEV~1~ at endpoint and at other times for treatment groups
during the treatment period. There was no impact on the inferential
statistical analysis for the primary efficacy parameter. This document
will review the data excluding Investigator #\[ \], but including
Investigator #\[ \], as presented in the sponsor's primary analysis.*

*Review of this study will focus on the efficacy of FP. Therefore
discussion will focus primarily on the comparison of FP 500 and placebo,
with less detailed review of comparisons of SAL 50 with SAL 50/FP 500
and SAL 50/FP 500 with placebo.*

#### Populations enrolled/analyzed

There were 1335 patients screened for the study. There were 661 patients
who were screening failures. A total of 674 patients were randomized.
The most common reason for screening failure was FEV~1~/FVC \<70% and
baseline FEV~1~ \<65% predicted but \>0.7 L (454/661, 69%). Other
reasons for screening failure included significant concurrent disease
(36/661, 5%), inability to tolerate the 2-week run-in (32/661, 5%),
moderate or severe COPD exacerbation during run-in (26/661, 4%),
abnormal and clinically significant 12-lead ECG (24/661, 4%), and
clinically significant chest X-ray abnormality, not due to COPD (21/661,
3%) \[clinstat\\copd\\sfca3006.pdf, pages 92, 1717-1720\].

*[Reviewer comment:]{.underline}*

*One might expect that failure to tolerate the 2-week run-in would be
the most common reason for screening failure in this study. However,
inability to meet the inclusion criterion for spirometry was the most
common reason for screening failure. This is probably the reason for the
change in Protocol Amendment 2 that changed FEV~1~/FVC ratio from ≤65%
to ≤70%. The most likely effect of this change would be to allow entry
of patients with milder obstruction. These patients might be more likely
to have reversibility, and might be more likely to respond to an inhaled
corticosteroid such as FP.*

Patient disposition is summarized in Table 11.2.3. There were 674
patients randomized and 440 patients completed the study. There were 234
patients that discontinued the study prematurely. The frequency of
discontinuations were fairly similar among treatment groups, with the
lowest frequency in SAL 50 (45/160, 28%). The most frequent reason for
discontinuation for all groups was COPD exacerbation. Among patients
discontinuing the study, there were 25% (17/68) who discontinued due to
COPD exacerbation in the FP 500 group, compared with 23%, (16/69) in the
placebo group, 27% (14/52) in the SAL 50/FP 500 group, and 20% (9/45) in
the SAL 50 group. The frequency of adverse events (AEs) leading to
discontinuation was highest in the FP 500 group (31%, 21/68), followed
by the placebo group (25%, 17/69), the SAL 50 grou0 (24%, 11/45), and
the SAL 50/FP 500 group (21%, 11/52). Lack of efficacy was a less
frequent reason for discontinuation in the FP 500 group (4%, 3/68) than
for SAL 50/FP 500 (6%, 3/52) SAL 50 (16%, 7/45) and placebo (16%, 11/69)
groups.

Table 11.2.3. Patient disposition, SFCA3006,
\[clinstat\\copd\\sfca3006.pdf, pages 93, 378\]

+-----------------+---------+---------+---------+---------+---------+
|                 | **Pl    | **SAL   | **FP    | **SAL   | **      |
|                 | acebo** | 50**    | 500**   | 50/FP   | Total** |
|                 |         |         |         | 500**   |         |
|                 | **N     | **N     | **N     |         | **N     |
|                 | (%)**   | (%)**   | (%)**   | **N     | (%)**   |
|                 |         |         |         | (%)**   |         |
+-----------------+---------+---------+---------+---------+---------+
| Patients        | 181     | 160     | 168     | 165     | 674     |
| randomized      | (100)   | (100)   | (100)   | (100)   | (100)   |
+-----------------+---------+---------+---------+---------+---------+
| Patients        | 112     | 115     | 100     | 113     | 440     |
| completed       | (62)    | (72)    | (60)    | (68)    | (65)    |
+-----------------+---------+---------+---------+---------+---------+
| Patients        | 69 (38) | 45 (28) | 68 (40) | 52 (32) | 234     |
| discontinued    |         |         |         |         | (35)    |
+-----------------+---------+---------+---------+---------+---------+
| Reason for      |         |         |         |         |         |
| discontinuation |         |         |         |         |         |
+-----------------+---------+---------+---------+---------+---------+
| Adverse event   | 17 (25) | 11 (24) | 21 (31) | 11 (21) | 60 (26) |
+-----------------+---------+---------+---------+---------+---------+
| COPD            | 16 (23) | 9 (20)  | 17 (25) | 14 (27) | 74 (32) |
| exacerbation    |         |         |         |         |         |
+-----------------+---------+---------+---------+---------+---------+
| Withdrawn       | 11 (16) | 4 (9)   | 5 (7)   | 10 (19  | 30 (13) |
| consent         |         |         |         | )       |         |
+-----------------+---------+---------+---------+---------+---------+
| Lack of         | 11 (16) | 7 (16)  | 3 (4)   | 3 (6)   | 24 (10) |
| efficacy        |         |         |         |         |         |
+-----------------+---------+---------+---------+---------+---------+
| Lost to         | 2 (3)   | 1 (2)   | 3 (4)   | 1 (2)   | 7 (3)   |
| follow-up       |         |         |         |         |         |
+-----------------+---------+---------+---------+---------+---------+
| Protocol        | 8 (12)  | 10 (22  | 14 (21) | 8 (15)  | 40 (17) |
| violation       |         | )       |         |         |         |
+-----------------+---------+---------+---------+---------+---------+
| Other           | 4 (6)   | 3 (7)   | 5 (7)   | 5 (10)  | 17 (7)  |
+-----------------+---------+---------+---------+---------+---------+
| Death\*         | 3\* (2) | 0 (0)   | 0 (0)   | 0 (0)   | 3 (1)   |
+-----------------+---------+---------+---------+---------+---------+

\*Deaths are also included in the adverse event category

#### Protocol deviations

The most common violations of inclusion and exclusion criteria included
significant concurrent disease and use of prohibited medications.
Significant concurrent disease ranged from 2% to 7%. Use of concurrent
medications that interfere with objective assessments ranged from 2% to
5% in the treatment groups \[clinstat\\copd\\sfca3006.pdf, pages 94,
383-385\].

*[Reviewer comment:]{.underline}*

*Violations of inclusion criteria were fairly infrequent and evenly
distributed between treatment groups and were not likely to affect the
analysis of efficacy or safety.*

There were few patients who varied from the protocol who were not
discontinued from the study, as presented in Table 11.2.4. The most
common protocol variations were use of a prohibited corticosteroid and
use of a prohibited non-corticosteroid medication
\[clinstat\\copd\\scfa3006.pdf, pages 94, 386\]. Other protocol
variations included significant concurrent disease, vital signs and
spirometry performed late or not performed
\[clinstat\\copd\\scfa3006.pdf, pages 2278-2285\].

Table 11.2.4. Protocol variations during conduct of the study, not
leading to discontinuation \[clinstat\\copd\\sfca3006.pdf, page 386\].

+---------------------+-----------+-----------+-----------+-----------+
|                     | **        | **SAL     | **FP      | **SAL     |
|                     | Placebo** | 50**      | 500**     | 50/FP     |
|                     |           |           |           | 500**     |
|                     | **N =     | **N =     | **N =     |           |
|                     | 181**     | 160**     | 168**     | **N =     |
|                     |           |           |           | 165**     |
|                     | **n (%)** |           | **n (%)** |           |
|                     |           |           |           | **n (%)** |
+=====================+===========+===========+===========+===========+
| All protocol        | 12 (7)    | 17 (11)   | 13 (8)    | 14 (8)    |
| variations          |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+
| Used a prohibited   | 3 (2)     | 4 (3)     | 3 (2)     | 3 (2)     |
| corticosteroid      |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+
| Used other          | 6 (3)     | 7 (4)     | 7 (4)     | 8 (5)     |
| prohibited          |           |           |           |           |
| medication          |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+
| Used pulmonary      | 0 (0)     | 0 (0)     | 0 (0)     | 1 (\<1)   |
| rehabilitation      |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+
| Used oxygen         | 0 (0)     | 1 (\<1)   | 0 (0)     | 0 (0)     |
+---------------------+-----------+-----------+-----------+-----------+
| Other               | 5 (3)     | 9 (6)     | 8 (5)     | 4 (2)     |
+---------------------+-----------+-----------+-----------+-----------+

As noted above, all \[ \] patients from Investigator #\[ \] were
excluded from study population and efficacy analyses. Of these \[ \]
patients, \[ \] were in the placebo group, \[ \]were in the SAL 50
group, \[ \] were in the FP 500 group, and \[ \] in the SAL 50/FP 500
group. There were 23 patients in the ITT group who only had only
baseline data for PFT, CBSQ, and TDI. These patients were not included
in the analyses for their respective endpoints. There were 11 patients
who had no baseline data for PFT, CBSQ, TDI, diary, or CRDQ. These
patients were excluded from the analyses of the endpoints were their
data was missing \[clinstat\\copd\\scfa3006.pdf, page 95\].

#### Demographic and background characteristics

Demographics and background characteristics of patients are displayed in
Table 11.2.5. The majority of patients in each of the treatment groups
were 65 years of age or older. The mean age of patients was 64 years in
the placebo group, 63.5 years in the SAL 50 group, 64.4 years in the FP
500 group, and 61.9 years in the SAL 50/FP 500 group. Patients ranged
from 40 to 90 years of age. The proportion of patients aged 65 years or
less was somewhat greater in the SAL 50/FP 500 group. The mean age was
also somewhat lower in the SAL 50/FP 500 group. The age range was
similar in each of the treatment groups.

The majority of patients in this study were of male gender. Males
represented from 61% to 75% of patients in each of the treatment groups.
There were proportionately more males in the placebo group. The
distribution of male and female patients was similar in the other
treatment groups. The vast majority of patients in this study were of
Caucasian race. There were few patients of Black or Asian race.
Non-Caucasian races represented 6% or less of each of the treatment
groups.

Patients in this study had fairly severe dyspnea. All patients
experienced dyspnea with walking on level ground, and approximately one
third of the patients in each of the treatment groups had dyspnea with
walking on level ground for 100 yards or worse (MMRC Dyspnea Score ≥3).
The patients in the placebo group had slightly milder dyspnea, with 71%
having a MMRC Dyspnea Score of 2, compared with 56% to 67% with MMRC
Dyspnea Scores of 2 in the other treatment groups. Mean duration of COPD
was approximately 7 years for each of the treatment groups. Duration of
COPD ranged from 1 year to 45 years.

There was a larger proportion of current smokers in the placebo group
(54%, 97/181) than the other treatment groups (56% for each group). The
placebo group had a larger median history of smoking (60.0 pack years)
than the other treatment groups (52.5 to 55.0 pack years). The median
history of smoking was much larger than the 20 pack-year history
required for entry into the study.

A smaller proportion of the placebo group (18%, 33/181) was using
inhaled corticosteroids at screening than the other treatment groups
(25%-31%). The majority of patients in each treatment group had
emphysema. The frequency of emphysema was similar among treatment groups
and ranged from 74% to 78%.

*[Reviewer comments:]{.underline}*

*The under-representation of non-Caucasian patients in this study is a
serious deficiency. The lack of Black, Asian, and Hispanic patients will
make it impossible to assess to efficacy or safety by race.*

*Overall, the population studied is characterized by long smoking
histories, significant dyspnea, and about an 8 year history of COPD. It
is unclear how the diagnosis of "emphysema" was made for the
approximately 75% of the patients who reported it, since the diagnosis
would require HRCT, DLCO, or an invasive procedure. The placebo group
has slightly higher percentage of patients with milder dyspnea. The
placebo group had a lower percentage of patients who were using inhaled
steroids at screening, a higher proportion of patients who were current
smokers, and had a slightly longer history of smoking. The effects of
these characteristics of the placebo group might be to favor the
demonstration of efficacy in the active treatment groups. These effects
may need to be considered if study results are not robust.*

*Overall, a fairly large minority of the patients was taking inhaled
corticosteroids at the time of screening. As noted earlier in this
review, one would expect these patients to more likely to be
corticosteroid-responsive than those not taking inhaled corticosteroids,
as one would expect patients with no response or a poor response to have
their treatment discontinued.*

Table 11.2.5. Demographics, SFCA3006 \[clinstat\\copd\\sfca3006.pdf,
pages 96, 387-391\].

+------------------+------------+------------+------------+------------+
| **               | *          | **SAL 50** | **FP 500** | **SAL      |
| Characteristic** | *Placebo** |            |            | 50/FP      |
|                  |            | **N =      | **N =      | 500**      |
|                  | **N =      | 160**      | 168**      |            |
|                  | 181**      |            |            | **N =      |
|                  |            |            |            | 165**      |
+==================+============+============+============+============+
| **Age, years**   | **n (%)**  |            | **n (%)**  | **n (%)**  |
+------------------+------------+------------+------------+------------+
| \<65             | 91 (50)    | 81 (51)    | 76 (45)    | 98 (59)    |
+------------------+------------+------------+------------+------------+
| ≥65              | 90 (50)    | 79 (49)    | 92 (55)    | 67 (41)    |
+------------------+------------+------------+------------+------------+
| Mean age         | 64.0       | 63.5       | 64.4       | 61.9       |
+------------------+------------+------------+------------+------------+
| SD               | 8.3        | 9.4        | 9.3        | 9.3        |
+------------------+------------+------------+------------+------------+
| Range            | 44 -- 90   | 40 -- 84   | 42 -- 82   | 40 -- 86   |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Gender**       | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
+------------------+------------+------------+------------+------------+
| Female           | 45 (25 )   | 57 (36)    | 65 (39)    | 62 (38)    |
+------------------+------------+------------+------------+------------+
| Male             | 136 (75)   | 103 (64)   | 103 (61)   | 103 (62)   |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Race**         | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
+------------------+------------+------------+------------+------------+
| Caucasian        | 166 (92)   | 152 (95)   | 156 (93)   | 156 (95)   |
+------------------+------------+------------+------------+------------+
| Black            | 11 (6)     | 6 (4)      | 8 (5)      | 7 (4)      |
+------------------+------------+------------+------------+------------+
| Asian            | 3 (2)      | 1 (\<1)    | 2 (1)      | 2 (1)      |
+------------------+------------+------------+------------+------------+
| Other            | 1 (\<1)    | 1 (\<1)    | 2 (1)      | 0 (0)      |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **MMRC Dyspnea   | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
| Score**          |            |            |            |            |
+------------------+------------+------------+------------+------------+
| 2                | 129 (71)   | 90 (56)    | 112 (67)   | 108 (65)   |
+------------------+------------+------------+------------+------------+
| 3                | 47 (26)    | 62 (39)    | 51 (30)    | 55 (33)    |
+------------------+------------+------------+------------+------------+
| 4                | 5 (3)      | 8 (5)      | 5 (3)      | 2 (1)      |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Duration of    | **Years**  | **Years**  | **Years**  | **Years**  |
| COPD**           |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Mean             | 8.00       | 7.84       | 8.18       | 8.10       |
+------------------+------------+------------+------------+------------+
| Range            | 1 -- 36    | 1 -- 46    | 1 -- 35    | 1 -- 41    |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Smoking        | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
| status**         |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Former smoker    | 84 (46)    | 86 (54)    | 91 (54)    | 89 (54)    |
+------------------+------------+------------+------------+------------+
| Current smoker   | 97 (54)    | 74 (46)    | 77 (46)    | 76 (46)    |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Pack-years     |            |            |            |            |
| smoked**         |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Median           | 60.0       | 52.5       | 54.0       | 55.0       |
+------------------+------------+------------+------------+------------+
| Range            | 20 -- 165  | 20 -- 193  | 20 -- 200  | 15 -- 150  |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Inhaled        | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
| steroids at      |            |            |            |            |
| screening**      |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Yes              | 33 (18)    | 49 (31)    | 42 (25)    | 46 (28)    |
+------------------+------------+------------+------------+------------+
| No               | 148 (82)   | 111 (69)   | 126 (75)   | 119 (72)   |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Emphysema**    | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
+------------------+------------+------------+------------+------------+
| Yes              | 142 (78)   | 125 (78)   | 125 (74)   | 123 (75)   |
+------------------+------------+------------+------------+------------+
| No               | 39 (22)    | 35 (22)    | 43 (26)    | 42 (25)    |
+------------------+------------+------------+------------+------------+

Patients had fairly severe airway obstruction. Spirometry results at the
time of screening are presented in Table 11.2.6. The mean FEV~1~ for
each treatment group of approximately 1250 mL, mean FEV~1~ % predicted
of about 41%, and mean FEV~1~/FVC % of about 48%. The degree of airway
obstruction was similar in each of the treatment groups
\[clinstat\\copd\\sfca3006.pdf, page 396\].

Table 11.2.6. Spirometry at screening, SFCA3006
\[clinstat\\copd\\sfca3006.pdf, page 396\].

+-------------+-------------+-------------+-------------+-------------+
|             | **Placebo** | **SAL 50**  | **FP 500**  | **SAL 50/FP |
|             |             |             |             | 500**       |
|             | **n = 181** | **n = 160** | **n = 168** |             |
|             |             |             |             | **N = 165** |
+-------------+-------------+-------------+-------------+-------------+
| **FEV~1~,   |             |             |             |             |
| mL**        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Mean        | 1317        | 1237        | 1233        | 1268        |
+-------------+-------------+-------------+-------------+-------------+
| SD          | 471         | 425         | 408         | 472         |
+-------------+-------------+-------------+-------------+-------------+
| Median      | 1220        | 1165        | 1145        | 1130        |
+-------------+-------------+-------------+-------------+-------------+
| Range       | 680 -- 2720 | 660 -- 2630 | 700 -- 2590 | 530 -- 2520 |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **FEV~1~, % |             |             |             |             |
| predicted** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Mean        | 41.48       | 40.25       | 41.40       | 40.85       |
+-------------+-------------+-------------+-------------+-------------+
| SD          | 12.44       | 11.54       | 11.91       | 11.91       |
+-------------+-------------+-------------+-------------+-------------+
| Median      | 40.76       | 40.17       | 40.77       | 41.56       |
+-------------+-------------+-------------+-------------+-------------+
| Range       | 18.1 --     | 18.4 --     | 19.4 --     | 20.5 --     |
|             | 90.0        | 71.6        | 64.9        | 65.1        |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| *           |             |             |             |             |
| *FEV~1~/FVC |             |             |             |             |
| %**         |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Mean        | 49.02       | 48.58       | 47.64       | 49.41       |
+-------------+-------------+-------------+-------------+-------------+
| SD          | 10.55       | 9.47        | 10.89       | 9.81        |
+-------------+-------------+-------------+-------------+-------------+
| Median      | 49.48       | 48.95       | 47.01       | 47.92       |
+-------------+-------------+-------------+-------------+-------------+
| Range       | 21.7 --     | 23.5 --     | 23.6 --     | 28.8 --     |
|             | 68.7        | 74.4        | 67.9        | 78.6        |
+-------------+-------------+-------------+-------------+-------------+

Patient response to treatment with bronchodilator at screening is
summarized in Table 11.2.7. A patient was considered "non-reversible"
if, after 4 puffs of Ventolin MDI, there was a change in FEV~1~ of \<12%
from baseline or there was \<200 mL absolute increase in the FEV~1~.
Therefore, a patient could be considered irreversible if they had a
change in FEV~1~ \< 200 cc associated with FEV~1~ \> 12% or FEV~1~ \>
200 cc associated with FEV~1~ \<12%. Reversible patients represented 59%
of all patients in this study. The mean % change in FEV~1~ for
reversible patients was 32.4%. Non-reversible patients represented 41 %
of all patients in this study. The mean % change in FEV~1~ for
non-reversible patients was 9.24%. The degree of reversibility in each
of the treatment groups was similar. The mean % change in FEV~1~ for all
patients was 22.9%.

*[Reviewer comment:]{.underline}*

*As with Study FLTA3025, the proportion of patients with reversibility
enrolled in this study is much higher than is found in the population of
COPD patients at large. There were 54% of patients in this study who had
reversibility. In addition, the degree of reversibility for the
reversible population was high---29.83%. As noted earlier in this
review, one would expect that only up to 30% of patients to have in
increase of ≥15% in FEV~1~ after inhalation of a beta-agonist.^1-4^ The
mean degree of reversibility in the non-reversible population was also
high---8.78%.*

*The high proportion of patients with reversibility in this study is a
critical consideration in determining whether the results of the study
can be generalized to the COPD population as a whole. Reversible
patients were over-represented relative to their prevalence in the COPD
population as a whole, and the degree of reversibility in these patients
is much higher than would be expected for the general population of
patients with COPD. As with FLTA3025, this may have a major impact on
the interpretation of the efficacy results of this study.*

**Table 11.2.7. Mean change in FEV~1~** after bronchodilator treatment
at screening\*, SFCA3006 \[clinstat\\copd\\sfca3006.pdf, pages 97,
397-398\].

  -------------------------------------------------------------------------------
                     **Placebo**   **SAL 50** **FP 500** **SAL50/FP   **All
                                                         500**        treatment
                                                                      groups**
  ------------------ ------------- ---------- ---------- ------------ -----------
  **Reversible                                                        
  patients**                                                          

  n (%)              101 (56)      82 (51)    90 (54)    88 (53)      361 (54)

  Mean % change in   28.05         31.55      28.56      31.56        29.83\*\*
  FEV~1~                                                              

  **Non-reversible                                                    
  (ATS) patients**                                                    

  n (%)              80 (44)       78 (49)    78 (46)    77 (47)      313 (46)

  Mean % change in   8.33          10.28      8.46       8.04         8.78\*\*
  FEV~1~                                                              

  **All patients**                                                    

  n (%)              181 (100)     160 (100)  168 (100)  165 (100)    674 (100)

  Mean % change in   19.33         21.18      19.23      20.58        20.05\*\*
  FEV~1~                                                              
  -------------------------------------------------------------------------------

\*Calculation of response: ([Post-BD FEV]{.underline}~1~ [minus Pre-BD
FEV]{.underline}~1~[) X 100]{.underline}

Pre-BD FEV~1~

> Not reversible if result is \<12% or \<200 mL increase in FEV~1~

Reversible if result is ≥12% and ≥200 mL increase in FEV~1~

\*\*Mean change derived from data for individual treatment group data

Compliance with study treatment was reported as high in this study.
These data are displayed in Table 11.2.8. More than 70% of patients in
each treatment group took 90% or more of the prescribed doses of
medication. The mean number of doses taken was approximately 93% in each
treatment group \[clinstat\\copd\\sfca3006.pdf, pages 99, 447\].

Table 11.2.8. Compliance with study treatment, SFCA3006
\[clinstat\\copd\\sfca3006.pdf, pages 99, 447\].

+-------------+-------------+-------------+-------------+-------------+
|             | **Placebo** | **SAL 50**  | **FP 500**  | **SAL 50/FP |
|             |             |             |             | 500**       |
|             | **n (%)**   | **n (%)**   | **n (%)**   |             |
|             |             |             |             | **n (%)**   |
+=============+=============+=============+=============+=============+
| All         | 181 (100)   | 160 (100)   | 168 (100)   | 165 (100)   |
| patients    |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| \<80%       | 19 (10)     | 14 (9)      | 14 (8)      | 14 (8)      |
| compliance  |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| 80-\<90%    | 33 (18)     | 21 (13)     | 25 (15)     | 22 (13)     |
| compliance  |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| ≥90%        | 126 (70)    | 123 (77)    | 127 (76)    | 126 (76)    |
| compliance  |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Missing     | 3 (2)       | 2 (1)       | 2 (1)       | 3 (2)       |
+-------------+-------------+-------------+-------------+-------------+

#### Primary efficacy endpoint

The primary efficacy endpoint was the mean change in FEV~1~ from
Baseline to study endpoint. As noted earlier in this review, this review
is concerned with the efficacy of FP in the treatment of COPD. Therefore
only pre-dose FEV~1~ measurements will be examined. The two-hour
post-dose FEV~1~ measurements were performed by the sponsor to help
assess the efficacy of SAL 50 and the contribution of SAL to the
efficacy of the combination SAL 50/FP 500 product, and these will not be
examined in this review. Data for the primary efficacy variable are
displayed in Table 11.2.9. and inferential analysis of the primary
efficacy variable is displayed in Table 11.2.10.

The mean change from baseline in FEV~1~ for the FP 500 group at endpoint
was 109 mL, which was 113 mL more than the placebo group at endpoint.
This comparison was statistically significant at p \<0.001. This change
corresponds to an effect size of 9.6%[^2]. Mean change from baseline in
FEV~1~ for the SAL 50/FP 500 group at endpoint was 156 mL, which was 49
mL more than the SAL 50 group. This comparison was statistically
different from the SAL 50 group at p = 0.012. Values for the mean change
in FEV~1~ from Baseline for the FP 500 group at Weeks 6, 12, and 24
ranged from 96 mL to 131 mL. Values for the mean change in FEV~1~ for
the placebo group at Weeks 6, 12, and 24 ranged from --18 mL to 15 mL.
Values for the mean change from baseline in FEV~1~ for the SAL 50/FP 500
group at Weeks 6, 12, and 24 ranged from 180 to 192 mL. Values for the
mean change from baseline in FEV~1~ for the SAL 50 group at weeks 6, 12,
and 24 ranged from 110 mL to 114 mL \[clinstat\\copd\\sfca3006.pdf,
pages 108, 512-521\].

Mean change from baseline in FEV~1~ for the FP 500 group at Weeks 1, 2,
3, 4, 8, 16, and 20 increased from 76 mL at Week 1 to 122 mL at Week 20
\[clinstat\\copd\\sfca3006.pdf, pages 108, 512-517\].

The mean percent change from baseline in FEV~1~ for FP 500 rose quickly
at the Week 1 visit, with a slow rise to endpoint levels over the
remaining course of treatment.

*[Reviewer comments:]{.underline}*

*Only the primary endpoint of change from baseline to endpoint in
pre-dose FEV~1~ , FP500 met the pre-defined criteria for efficacy. FP
was numerically better than placebo at endpoint and for the interim time
points in the course of therapy. All three active treatments showed
clinically significant differences from placebo at Week 1. The rapid
increase from baseline in FEV~1~ for FP 500 is somewhat of a surprise,
as one would have expected a slower rise for an inhaled corticosteroid.
This rapid increase is likely to be a manifestation of the high dose of
FP used in this study. The slower rise from Week 1 to endpoint levels
for FP 500 is more representative of the expected response to inhaled
corticosteroids.*

**Table 11.2.9. Mean change in pre-dose FEV~1~ from baseline, primary
efficacy variable, SFCA3006 \[clinstat\\copd\\sfca3006.pdf, pages 108,
512-521\].**

  ---------------- --------- ----------- ------- --------- ----------- ------- --------- ----------- ------- --------- ----------- -------
                   **Pbo**                       **SAL                         **FP                          **SAL                 
                                                 50**                          500**                         50/FP                 
                                                                                                             500**                 

  **Study week**   **Mean    **Mean      **n**   **Mean    **Mean      **n**   **Mean    **Mean      **n**   **Mean    **Mean      **n**
                   FEV~1~,   change from         FEV~1~,   change from         FEV~1~,   change from         FEV~1~,   change from 
                   mL**      baseline,           mL**      baseline,           mL**      baseline,           mL**      baseline,   
                             mL**                          mL**                          mL**                          mL**        

  **Baseline**     1282      NA          181     1192      NA          159     1174      NA          166     1254      NA          163

  **Week 6**       1338      15          141     1329      114         138     1295      96          141     1440      192         142

  **Week 12**      1334      -12         127     1340      110         131     1289      81          121     1440      186         132

  **Week 24**      1344      -18         112     1383      116         114     1362      131         99      1432      180         113

  **Endpoint\***   1292      -4          171     1303      107         158     1298      109         161     1410      156         157
  ---------------- --------- ----------- ------- --------- ----------- ------- --------- ----------- ------- --------- ----------- -------

\*Primary efficacy endpoint

**Table 11.2.10. Inferential analysis of baseline and change from
baseline in pre-dose FEV~1~**, primary efficacy variable, SFCA3006,
\[clinstat\\copd\\sfca3006.pdf, pages 518-521\].

+---------+--------------+--------------+--------------+--------------+
| **Study | **Overall**  | **Pbo**      | **Pbo**      | **SAL 50**   |
| week**  |              |              |              |              |
|         | **p          | **vs. FP     | **vs. SAL    | **vs. SAL    |
|         | value\***    | 500**        | 50/FP 500**  | 50/FP 500**  |
|         |              |              |              |              |
|         |              | **p          | **p          | **p          |
|         |              | value\***    | value\***    | value\***    |
+---------+--------------+--------------+--------------+--------------+
| Endpo   | \<0.001      | \<0.001      | \<0.001      | 0.012        |
| int\*\* |              |              |              |              |
+---------+--------------+--------------+--------------+--------------+

\*ANCOVA, Baseline as covariate

\*\*Primary efficacy endpoint

#### Secondary efficacy endpoints

Secondary efficacy variables included change from baseline in the global
and individual domains of the CBSQ, the BDI/TDI score at each of the
treatment visits, number and percent of exacerbations of COPD, time to
first COPD exacerbation, number of withdrawals and time to withdrawals.
Morning PEFR, daily use of Ventolin, percentage of nights with no
awakenings requiring Ventolin, frequency of nighttime awakenings
requiring Ventolin, and percent of days without using Ventolin were also
summarized. The CRDQ was also used to compare changes in the
COPD-related quality of life for treatment groups as measured by an
overall score and for each of the four domains.

Summary statistics were provided for all secondary endpoints. Changes
from baseline in the Global Assessment Score (GAS) of the CBSQ were
compared between treatment groups using an ANCOVA F-test with treatment
group, investigator, and baseline value as covariates. Overall and
pairwise treatment comparisons of the BDI/TDI scores were performed by
ANOVA F-test. Time to first COPD exacerbation, number of withdrawals,
and time to withdrawals were analyzed using survival analysis
\[clinstat\\copd\\sfca3006.pdf, pages 11854-11855\]. For the CRDQ,
treatment group comparisons were made comparing the change from baseline
at each visit using ANCOVA, controlling for baseline and investigator
\[clinstat\\copd\\sfca3006.pdf, pages 11855-11866\].

*[Reviewer comment]{.underline}:*

*Inferential analysis is appropriate only for the prospectively defined
efficacy endpoint on which the study was powered, and not for these
secondary efficacy endpoints. Therefore, this document will focus on the
numerical differences between treatment groups for the secondary
efficacy endpoints, and will not address the inferential statistical
analysis.*

##### Chronic Bronchitis Symptom Questionnaire

The CBSQ evaluated cough frequency and severity, sputum release, and
chest discomfort on a 0 to 4, 5-point scale. Individual scores were
summed to provide a Global Assessment Score (GAS). The maximum possible
GAS was 16 \[clinstat\\copd\\sfca3006.pdf, page 116\]. Patients were
required to have a minimum score of 4 at baseline to qualify for
randomization. The sponsor determined that the Minimally Clinically
Important Change (MCIC) in the CBSQ was 1.4 points in an analysis of
patients completing at least 8 weeks of this study
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 11\]. Results of the
Chronic Bronchitis Symptom Questionnaire are displayed in Table 11.2.11.
The sponsor reported clinically important decreases in the CBSQ for FP
500 at Week 3 through Week 24 and at endpoint. The sponsor reported
clinically important decreases in the CBSQ for SAL 50 and SAL 50/FP 500
at endpoint and Week 2 through Week 24. The sponsor reported clinically
important decreases in the CBSQ for the placebo group at Weeks 8, 16,
24, and

**Table 11.2.11. Chronic Bronchitis Symptom Questionnaire, SFCA3006. See
text for comments. \[clinstat\\copd\\sfca3006.pdf, pages 117,
574-579\]**

  -------------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ -------
                 **Pbo**                          **SAL 50**                       **FP 500**                       **SAL 50/FP              
                                                                                                                    500**                    

  **Study week** **GAS\***   **Mean       **n**   **GAS\***   **Mean       **n**   **GAS\***   **Mean       **n**   **GAS\***   **Mean       **n**
                             change from                      change from                      change from                      change from  
                             baseline**                       baseline**                       baseline**                       baseline**   

  **Baseline**   7.3         NA           180     7.4         NA           159     7.0         NA           167     6.9         NA           164

  **Week 1**     6.7         0.5          169     6.2         1.2          157     5.9         1.1          161     5.6         1.3          157

  **Week 2**     6.3         0.8          156     5.9         1.4          152     5.7         1.3          157     5.4         1.5          153

  **Week 3**     6.1         1.0          154     5.6         1.8          143     5.6         1.5          150     5.0         1.8          149

  **Week 4**     5.8         1.3          148     5.4         1.9          141     5.6         1.6          148     5.3         1.6          147

  **Week 6**     5.9         1.2          141     5.7         1.6          139     5.3         1.8          141     4.9         1.9          142

  **Week 8**     5.3         1.8          142     5.7         1.7          134     5.2         1.9          138     4.8         2.1          139

  **Week 12**    5.7         1.3          127     5.6         1.8          131     5.0         2.0          120     4.8         2.1          132

  **Week 16**    5.6         1.4          119     5.4         1.9          124     5.2         1.8          108     5.3         1.5          126

  **Week 20**    5.9         1.1          113     5.3         2.1          120     5.2         1.9          103     4.6         2.2          116

  **Week 24**    5.4         1.6          112     4.9         2.4          115     5.2         1.9          100     4.8         2.1          112

  **Endpoint**   5.7         1.5          172     5.5         1.9          158     5.5         1.6          161     5.1         1.8          157
  -------------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ -------

\*GAS: Global Assessment Score. Minimally clinically important change =
1.4 points.

at endpoint. Decreases in the CBSQ for active treatment groups were
numerically superior to placebo at all visits and at endpoint, except
for Week 8. Improvements in the CBSQ were not clinically significantly
different from improvements noted in the placebo group for any of the
active treatment groups at any time, however
\[clinstat\\copd\\sfca3006.pdf, pages 117, 574-579\].

*[Reviewer comment:]{.underline}*

*Small decreases in the CBSQ were noted for FP 500, SAL 50, and SAL
50/FP 500 at Weeks 3 to 24 and at endpoint. In general, changes were
numerically superior to placebo. However, the differences from placebo
for all active treatment groups were less than the MCIC of 1.4 points.*

##### Baseline/Transition Dyspnea Indices

The degree of functional impairment at baseline due to dyspnea, the
magnitude of task to provoke dyspnea, and the magnitude of effort that
provoked dyspnea were rated on a 0 to 4, 5-point scale to derive the
BDI. The maximum BDI score was 12. The TDI assessed changes from
baseline in functional impairment, magnitude of task, and magnitude of
effort were assessed at each subsequent visit with a -3 to +3,
seven-point scale \[clinstat\\copd\\sfca3006.pdf, page 61-67\]. The
sponsor considered a clinically important TDI score to be ≥1.0
\[clinstat\\copd\\sfca3006.pdf, page 118, Correspondence submitted to
IND 50,703, Meeting request package, 2/6/98\].

Results of the BDI/TDI are presented in Table 11.2.12. All treatment
groups, including placebo, had clinically significant changes from
baseline, however, the differences between the FP 500 TDIs and placebo
were greater than the minimal clinically significant TDI of 1.0 point at
Week 24 only \[clinstat\\copd\\sfca3006.pdf, pages 119, 588-591\].

*[Reviewer comment:]{.underline}*

*The population studied included a high percentage of patients with
reversibility with bronchodilator and does not accurately represent the
population of COPD patients. Degree of functional impairment, magnitude
of task, and magnitude of effort are likely to be highly correlated
variables, in this reviewer's opinion, and therefore will tend to
inflate any observed positive or negative treatment effect. This
instrument has not been validated in a COPD population with a high
degree of reversibility, and it is not a widely used scale or one that
is held in high regard. These data do not provide support for the
efficacy of FP.*

**Table 11.2.12. Baseline/Transition Dyspnea Index (BDI/TDI), SFCA3006.
See text for comments. \[clinstat\\copd\\sfca3006.pdf, pages 119,
588-591\]**

  -------------- ----------- --------- ------- --------- ------- --------- ------- --------- -------
                             **Pbo**           **SAL             **FP              **SAL     
                                               50**              500**             50/FP     
                                                                                   500**     

  **Study week** **BDI**               **n**   **BDI**   **n**   **BDI**   **n**   **BDI**   **n**

  **Baseline**   5.8                   179     5.9       154     6.0       164     6.2       160

                 **TDI\***             **n**   **TDI**   **n**   **TDI**   **n**   **TDI**   **n**

  **Week 1**     0.1                   169     1.0       157     0.8       161     1.6       157

  **Week 2**     0.3                   156     0.9       152     0.9       157     1.4       153

  **Week 3**     0.9                   154     1.2       143     1.2       150     1.4       149

  **Week 4**     0.9                   148     1.1       141     1.3       148     1.6       147

  **Week 6**     0.9                   141     1.1       139     1.0       141     2.0       142

  **Week 8**     1.2                   142     1.4       134     1.5       138     2.4       139

  **Week 12**    0.6                   127     1.3       131     1.4       120     2.0       132

  **Week 16**    0.5                   119     1.4       124     1.3       108     1.9       126

  **Week 20**    0.4                   113     1.7       120     1.6       103     2.4       117

  **Week 24**    0.6                   112     1.6       116     1.9       100     2.7       113

  **Endpoint**   0.4                   172     0.9       158     1.3       161     2.1       157
  -------------- ----------- --------- ------- --------- ------- --------- ------- --------- -------

\*Minimally clinically significant TDI = 1.0 point.

##### COPD exacerbations

The incidence of COPD exacerbation was similar for all treatment groups.
The incidence of moderate to severe COPD exacerbations was similar for
all treatment groups. Moderate to severe exacerbations of COPD were
defined as those requiring oral antibiotics, inhaled or oral
corticosteroids, or inpatient admission for treatment. These data are
displayed in Table 11.2.13.

*[Reviewer comment:]{.underline}*

*It is important to note that the definition of COPD exacerbation was
not the standard definition. The sponsor's definition of COPD
exacerbation describes situations that reflect a worsening of airway
bronchoconstriction, and would be likely to favor the finding of
efficacy of FP in patients who have a high degree of reversibility. Even
so, and despite the improvements in FEV~1~ noted, patients treated with
active drug had similar incidences of COPD exacerbations to patients
treated with placebo.*

Table 11.2.13. Incidence of COPD exacerbations, SFCA3006
\[clinstat\\copd\\sfca3006.pdf, pages 122, 613-614\].

+------------------------+----------+----------+----------+----------+
|                        | **P      | **SAL    | **FP     | **SAL    |
|                        | lacebo** | 50**     | 500**    | 50/FP    |
|                        |          |          |          | 500**    |
|                        | **N =    | **N =    | **N =    |          |
|                        | 181**    | 160**    | 168**    | **N =    |
|                        |          |          |          | 165**    |
|                        | **n      | **n      | **n      |          |
|                        | (%)**    | (%)**    | (%)**    | **n      |
|                        |          |          |          | (%)**    |
+------------------------+----------+----------+----------+----------+
| Patients with any COPD | 79 (44)  | 63 (39)  | 77 (46)  | 68 (41)  |
| exacerbation           |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| Patients with moderate | 63 (35)  | 60 (38)  | 67 (40)  | 61 (37)  |
| or severe COPD         |          |          |          |          |
| exacerbations          |          |          |          |          |
+------------------------+----------+----------+----------+----------+

Time to COPD exacerbation or withdrawal is summarized in Table 11.2.14.
In general, first COPD exacerbations, first moderate to severe COPD
exacerbations, study withdrawals, and withdrawals due to COPD
exacerbation were similar in the FP 500 and placebo groups.

*[Reviewer comment:]{.underline}*

*These data provide no support for the efficacy of FP in the population
studied.*

Table 11.2.14. Time to COPD exacerbation or withdrawal, SFCA3006

+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| *     |       |       |       |       |       |       |       |       |
| *Time |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| First |       |       |       |       |       |       |       |       |
| COPD  |       |       |       |       |       |       |       |       |
| Ex    |       |       |       |       |       |       |       |       |
| acerb |       |       |       |       |       |       |       |       |
| ation |       |       |       |       |       |       |       |       |
| \     |       |       |       |       |       |       |       |       |
| [clin |       |       |       |       |       |       |       |       |
| stat\ |       |       |       |       |       |       |       |       |
| \copd |       |       |       |       |       |       |       |       |
| \\sfc |       |       |       |       |       |       |       |       |
| a3006 |       |       |       |       |       |       |       |       |
| .pdf, |       |       |       |       |       |       |       |       |
| pages |       |       |       |       |       |       |       |       |
| 6     |       |       |       |       |       |       |       |       |
| 16-61 |       |       |       |       |       |       |       |       |
| 9\]** |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **    |       | **SAL |       | **FP  |       | **SAL |       |
|       | Pbo** |       | 50**  |       | 500** |       | 50/** |       |
|       |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       | **FP  |       |
|       |       |       |       |       |       |       | 500** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve |
|       | ients | nts** | ients | nts** | ients | nts** | ients | nts** |
|       | at    |       | at    |       | at    |       | at    |       |
|       | r     |       | r     |       | r     |       | r     |       |
|       | isk** |       | isk** |       | isk** |       | isk** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 135   | 32    | 132   | 21    | 131   | 29    | 134   | 20    |
| 1     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 109   | 50    | 113   | 34    | 101   | 50    | 114   | 36    |
| 2     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 91    | 63    | 96    | 49    | 86    | 59    | 104   | 44    |
| 3     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 81    | 69    | 91    | 53    | 76    | 64    | 89    | 55    |
| 4     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 72    | 76    | 87    | 56    | 61    | 74    | 78    | 61    |
| 5     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 0     | 78    | 0     | 62    | 0     | 77    | 0     | 67    |
| 6     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| *     |       |       |       |       |       |       |       |       |
| *Time |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| First |       |       |       |       |       |       |       |       |
| Mod   |       |       |       |       |       |       |       |       |
| erate |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| S     |       |       |       |       |       |       |       |       |
| evere |       |       |       |       |       |       |       |       |
| COPD  |       |       |       |       |       |       |       |       |
| Ex    |       |       |       |       |       |       |       |       |
| acerb |       |       |       |       |       |       |       |       |
| ation |       |       |       |       |       |       |       |       |
| \     |       |       |       |       |       |       |       |       |
| [clin |       |       |       |       |       |       |       |       |
| stat\ |       |       |       |       |       |       |       |       |
| \copd |       |       |       |       |       |       |       |       |
| \\sfc |       |       |       |       |       |       |       |       |
| a3006 |       |       |       |       |       |       |       |       |
| .pdf, |       |       |       |       |       |       |       |       |
| pages |       |       |       |       |       |       |       |       |
| 6     |       |       |       |       |       |       |       |       |
| 21-62 |       |       |       |       |       |       |       |       |
| 4\]** |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **    |       | **SAL |       | **FP  |       | **SAL |       |
|       | Pbo** |       | 50**  |       | 500** |       | 50/** |       |
|       |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       | **FP  |       |
|       |       |       |       |       |       |       | 500** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve |
|       | ients | nts** | ients | nts** | ients | nts** | ients | nts** |
|       | at    |       | at    |       | at    |       | at    |       |
|       | r     |       | r     |       | r     |       | r     |       |
|       | isk** |       | isk** |       | isk** |       | isk** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 147   | 16    | 136   | 15    | 140   | 19    | 139   | 15    |
| 1     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 123   | 32    | 117   | 28    | 113   | 37    | 118   | 32    |
| 2     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 104   | 45    | 98    | 45    | 98    | 46    | 109   | 39    |
| 3     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 91    | 53    | 92    | 50    | 85    | 52    | 94    | 50    |
| 4     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 81    | 60    | 88    | 53    | 68    | 64    | 83    | 55    |
| 5     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 0     | 62    | 0     | 59    | 0     | 67    | 0     | 60    |
| 6     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| *     |       |       |       |       |       |       |       |       |
| *Time |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| Study |       |       |       |       |       |       |       |       |
| Withd |       |       |       |       |       |       |       |       |
| rawal |       |       |       |       |       |       |       |       |
| \[cl  |       |       |       |       |       |       |       |       |
| insta |       |       |       |       |       |       |       |       |
| t\\co |       |       |       |       |       |       |       |       |
| pdsfc |       |       |       |       |       |       |       |       |
| a3006 |       |       |       |       |       |       |       |       |
| .pdf, |       |       |       |       |       |       |       |       |
| pages |       |       |       |       |       |       |       |       |
| 6     |       |       |       |       |       |       |       |       |
| 26-62 |       |       |       |       |       |       |       |       |
| 9\]** |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **    |       | **SAL |       | **FP  |       | **SAL |       |
|       | Pbo** |       | 50**  |       | 500** |       | 50/** |       |
|       |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       | **FP  |       |
|       |       |       |       |       |       |       | 500** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve |
|       | ients | nts** | ients | nts** | ients | nts** | ients | nts** |
|       | at    |       | at    |       | at    |       | at    |       |
|       | r     |       | r     |       | r     |       | r     |       |
|       | isk** |       | isk** |       | isk** |       | isk** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 156   | 25    | 149   | 11    | 157   | 11    | 151   | 14    |
| 1     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 143   | 38    | 138   | 22    | 141   | 27    | 142   | 23    |
| 2     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 136   | 45    | 132   | 28    | 131   | 37    | 138   | 27    |
| 3     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 124   | 57    | 129   | 31    | 117   | 51    | 133   | 32    |
| 4     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 116   | 65    | 124   | 36    | 105   | 63    | 121   | 44    |
| 5     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 0     | 68    | 0     | 41    | 0     | 65    | 0     | 50    |
| 6     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| *     |       |       |       |       |       |       |       |       |
| *Time |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| Study |       |       |       |       |       |       |       |       |
| Withd |       |       |       |       |       |       |       |       |
| rawal |       |       |       |       |       |       |       |       |
| due   |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| COPD  |       |       |       |       |       |       |       |       |
| Ex    |       |       |       |       |       |       |       |       |
| acerb |       |       |       |       |       |       |       |       |
| ation |       |       |       |       |       |       |       |       |
| \     |       |       |       |       |       |       |       |       |
| [clin |       |       |       |       |       |       |       |       |
| stat\ |       |       |       |       |       |       |       |       |
| \copd |       |       |       |       |       |       |       |       |
| \\sfc |       |       |       |       |       |       |       |       |
| a3006 |       |       |       |       |       |       |       |       |
| .pdf, |       |       |       |       |       |       |       |       |
| pages |       |       |       |       |       |       |       |       |
| 6     |       |       |       |       |       |       |       |       |
| 31-63 |       |       |       |       |       |       |       |       |
| 4\]** |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **    |       | **SAL |       | **FP  |       | **SAL |       |
|       | Pbo** |       | 50**  |       | 500** |       | 50/** |       |
|       |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       | **FP  |       |
|       |       |       |       |       |       |       | 500** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve |
|       | ients | nts** | ients | nts** | ients | nts** | ients | nts** |
|       | at    |       | at    |       | at    |       | at    |       |
|       | r     |       | r     |       | r     |       | r     |       |
|       | isk** |       | isk** |       | isk** |       | isk** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 156   | 7     | 149   | 2     | 157   | 2     | 151   | 3     |
| 1     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 143   | 11    | 138   | 4     | 141   | 9     | 142   | 8     |
| 2     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 136   | 12    | 132   | 7     | 131   | 13    | 138   | 9     |
| 3     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 124   | 17    | 129   | 8     | 117   | 20    | 133   | 10    |
| 4     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 116   | 20    | 124   | 10    | 105   | 24    | 121   | 15    |
| 5     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 0     | 21    | 0     | 12    | 0     | 26    | 0     | 18    |
| 6     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+

##### PEFR

PEFR data are presented in Table 11.2.15. Overall, there was a small
mean increase from baseline in AM PEFR was for the FP 500 (12.9 L/min)
and SAL 50 (16.8 L/min) groups at the end of the study. A larger mean
increase was observed in the SAL 50/FP 500 group (31.9 L/min). Similar
increases from baseline in AM PEFR was noted for FP 500, SAL 50, and SAL
50/FP 500 at the end of each month during the treatment period. The
increases ranged from 7.2 L/min at Month 1 to 22.0 L/min at Month 6
\[clinstat\\copd\\sfca3006.pdf, pages 125, 641-644\].

*[Reviewer comment:]{.underline}*

*Small increases in AM PEFR for the FP 500 group and the SAL 50/FP 500
group compared with placebo and SAL 50 give support for efficacy of FP
500 in this population and are concordant with the findings of the
primary endpoint of change from baseline in pre-dose FEV~1~.*

Table 11.2.15. Mean change from baseline in AM PEFR
\[clinstat\\copd\\sfca3006.pdf, pages 125, 641-644\].

  ------------------------ ------------- ----------- ----------- -----------
                           **Placebo**   **SAL 50**  **FP 500**  **SAL 50/FP
                                                                 500**

  **Baseline**                                                   

  N                        181           158         167         162

  Mean PEFR, L/min         269.5         252.1       243.7       254.0

  **Overall**                                                    

  N                        179           157         166         162

  Mean PEFR, L/min         267.1         268.7       256.6       284.7

  Mean change from         -2.7          16.8        12.9        31.9
  baseline, L/min                                                
  ------------------------ ------------- ----------- ----------- -----------

##### Supplemental Ventolin use

Supplemental Ventolin use is summarized in Table 11.2.16. Overall, the
FP 500 and SAL 50, and SAL 50/FP 500 groups had small decreases in the
number of puffs of Ventolin used per day. The decrease for FP 500 was
much less than that for SAL 50 or for SAL 50/FP 500. The decrease in
Ventolin use for FP 500 ranged from 0.2 to 0.6 puffs per day for each
study month. Overall, the FP 500, SAL 50, and SAL 50/FP 500 groups had
increases in the number of days without Ventolin use. The decrease for
FP 500 was less than that for SAL 50 or for SAL 50/FP 500. The decrease
in Ventolin use for FP 500 ranged from 4.1% to 7.9% for each study
month.

Table 11.2.16. Mean change from baseline in supplemental Ventolin use
\[clinstat\\copd\\sfca3006.pdf, pages 126, 646-653\]

+------------------------+----------+----------+----------+----------+
|                        | **P      | **SAL    | **FP     | **SAL    |
|                        | lacebo** | 50**     | 500**    | 50/FP    |
|                        |          |          |          | 500**    |
+========================+==========+==========+==========+==========+
| **Number of puffs of   |          |          |          |          |
| Ventolin used per      |          |          |          |          |
| day**                  |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| **Baseline**           |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| N                      | 181      | 158      | 166      | 161      |
+------------------------+----------+----------+----------+----------+
| Mean number of puffs   | 4.9      | 4.6      | 4.5      | 4.2      |
+------------------------+----------+----------+----------+----------+
| **Overall**            |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| N                      | 179      | 157      | 164      | 161      |
+------------------------+----------+----------+----------+----------+
| Mean number of puffs   | 5.4      | 3.6      | 4.1      | 3.0      |
+------------------------+----------+----------+----------+----------+
| Mean change from       | 0.5      | -0.9     | -0.4     | -1.2     |
| baseline, puffs        |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| **Percent of days      |          |          |          |          |
| without Ventolin use** |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| **Baseline**           |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| N                      | 181      | 158      | 166      | 161      |
+------------------------+----------+----------+----------+----------+
| Mean % days without    | 19.0     | 21.4     | 22.1     | 28.0     |
| Ventolin use           |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| **Overall**            |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| N                      | 179      | 159      | 165      | 165      |
+------------------------+----------+----------+----------+----------+
| Mean % days without    | 19.5     | 31.0     | 28.5     | 43.7     |
| Ventolin use           |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| Mean change from       | 0.3      | 9.3      | 6.2      | 16.3     |
| baseline,              |          |          |          |          |
|                        |          |          |          |          |
| \% days                |          |          |          |          |
+------------------------+----------+----------+----------+----------+

Nighttime awakenings requiring Ventolin use are summarized in Table
11.2.17. Overall, the FP 500, SAL 50, and SAL 50/FP 500 groups had very
small decreases from baseline in the number of awakenings per night.
Overall the FP 500, SAL 50, and SAL 50/FP 500 groups had small increases
in the percent of nights with no awakenings requiring Ventolin use. Of
the active treatment groups, the FP 500 group had the smallest increase
in percent of nights with no awakenings.

*[Reviewer comment:]{.underline}*

*The small changes from baseline in nighttime awakenings and percent of
nights with no awakenings requiring Ventolin provide some weak support
of the efficacy of FP 500 in this population.*

Table 11.2.17. Mean change from baseline in nighttime awakenings
requiring Ventolin use \[clinstat\\copd\\sfca3006.pdf, pages 128-129\]

  --------------------------------------------------------------------------
                           **Placebo**   **SAL 50**  **FP 500**  **SAL 50/FP
                                                                 500**
  ------------------------ ------------- ----------- ----------- -----------
  **Number of awakenings                                         
  per night requiring                                            
  Ventolin**                                                     

  **Baseline**                                                   

  N                        177           156         163         157

  Mean number of           0.27          0.26        0.24        0.22
  awakenings                                                     

  **Overall**                                                    

  N                        175           153         162         157

  Mean number of           0.36          0.17        0.16        0.19
  awakenings                                                     

  Mean change from         0.10          -0.09       -0.08       -0.04
  baseline, awakenings                                           

  **Percent of nights with                                       
  no awakenings requiring                                        
  Ventolin**                                                     

  **Baseline**                                                   

  N                        177           156         163         157

  Mean % nights with no    82.9          82.2        86.4        84.4
  awakenings                                                     

  **Overall**                                                    

  N                        177           157         165         163

  Mean % nights with no    78.9          89.0        89.5        89.8
  awakenings                                                     

  Mean change from         -4.3          6.8         3.0         5.7
  baseline, % nights with                                        
  no awakenings                                                  
  --------------------------------------------------------------------------

##### 12-hour serial spirometry

The sponsor performed 12-hour serial spirometry at Day 1 and Week 12 in
a subset of patients at selected sites to demonstrate that SAL 50- and
SAL 50/FP 500-induced increases were sustained for 12 hours
\[clinstat\\copd\\sfca3006.pdf, pages 113, 11854\]. This secondary
efficacy endpoint was chosen to support the SAL 50 and SAL 50/FP 500
applications, and is not pertinent to the FP 500 application. This
secondary endpoint will not be reviewed in this document.

##### Health-related quality of life instrument

QOL assessment was one of the pre-specified objectives of this study.
COPD-related quality of life was evaluated using the Chronic Respiratory
Disease Questionnaire (CRDQ).^10^ The CRDQ contains 20 questions in 4
domains: dyspnea, fatigue, emotional function, and mastery. An overall
score, the sum of the scores for all 20 questions, was the primary
health-related quality of life endpoint. A physical score was calculated
based on the sum of scores in the dyspnea and fatigue domains and an
emotional score was calculated based on the sum of scores of the
emotional function and mastery domains \[clinstat\\copd\\sfca3006.pdf,
page 87\]. A clinically significant improvement was considered to be 0.5
points per item. Therefore, an improvement in the Overall score of at
least 10.0 points was considered to be a clinically significant
improvement in COPD-specific quality of life. As there were different
numbers of items per domain, the clinically significant changes for each
domain and summary scores are as follows \[clinstat\\copd\\sfca3006.pdf,
pages 86-88\]:

-   Fatigue domain: 2.0 points

-   Dyspnea domain: 2.5 points

```{=html}
<!-- -->
```
-   Physical summary: 4.5 points

```{=html}
<!-- -->
```
-   Emotional function domain: 3.5 points

-   Mastery domain: 2.0 points

-   Emotional summary: 5.5 points

Study endpoint was defined as the last available post-baseline score for
the CDRQ. This was different from the other analyses, which did not
include values for the Discontinuation visit
\[clinstat\\copd\\sfca3006.pdf, page 160\]. In addition, the sponsor
excluded patients with an overall baseline score greater than 130 from
the analysis of the overall score at any visit. These patients were
excluded because baseline scores would be mathematically unable to
attain a clinically meaningful change \[clinstat\\copd\\sfca3006.pdf,
page 161\]. Similar exclusions were made for the patients with the
following scores \[clinstat\\copd\\sfca3006.pdf, page 87\]:

-   Fatigue score \>26

```{=html}
<!-- -->
```
-   Dyspnea score \>32

-   Physical summary \>58

-   Emotional function score \>45

-   Mastery score \>26

-   Emotional summary \>71

The population analyzed, which excluded these patients, was referred to
the "reduced intent-to-treat population" (reduced ITT population)
\[clinstat\\copd\\sfca3006.pdf, page 87\].

*[Reviewer comment:]{.underline}*

*It is true that it is be mathematically impossible for patients whose
baseline scores are higher than those noted above to attain a clinically
meaningful change. However, it is not appropriate to exclude these
patients from the analysis. It would have been preferable to set these
maximum scores as inclusion criteria for the study. As it turns out,
there were no patients excluded for the Overall score and the Dyspnea
domain score and the ITT and "reduced ITT populations" were identical
for these scores \[clinstat\\copd\\sfca3006.pdf, pages 161, 1134, 2009,
2105\].*

*There were a total of 27 patients among all treatment groups excluded
from the calculation of the Emotional summary score and 1 patient
excluded from the Physical summary score. There were 25 patients
excluded from the Emotional function domain score, 62 patients from the
Mastery domain score, and 4 patients from the Fatigue domain score
\[clinstat\\copd\\sfca3006.pdf, pages 1134, 1140, 1146, 1152, 1158,
1164, 2015, 2021, 2027, 2033, 2039, 2045\]. This review will examine
CDRQ results for the ITT group and not the reduced ITT population.*

There was a small, clinically significant increase from baseline in the
overall CDRQ score for SAL 50/FP 500 only (10.0 points). However, the
change in the overall CDRQ score for SAL 50/FP 500 was less than a 10.0
point difference from the change in the placebo group, and therefore was
not a clinically significant difference from the placebo group. The
increase in the overall CDRQ score for FP 500 (4.8 points) was similar
to placebo (5.0 points), less than the specified clinically significant
change of 10.0 points. These data are displayed in Table 11.2.18. The
data displayed reflects the ITT population. Only SAL 50/FP 500 had a
small, clinically significant increase from baseline in the Physical
summary score (6.1 points). However, this increase was not clinically
significantly different than the placebo group, as there was less than a
4.5 point difference between them. The increase in the Physical summary
score for FP 500 (3.4 points) was slightly greater than to placebo (2.7
points), but less than the specified clinically significant change of
4.5 points. No treatment group had a clinically significant increase
from baseline in the Emotional summary score
\[clinstat\\copd\\sfca3006.pdf, pages 2009, 2027, 2045\].

In general, individual domains showed small, but not clinically
significant increases from baseline for SAL 50 and FP 500. Exceptions
included the Dyspnea domain, which showed small clinically significant
increases from baseline for SAL 50 and SAL 50/FP 500. These increases
were less than a 2.5 point difference from the change for the placebo
group, and therefore not clinically significantly different than the
placebo group. The Emotional function and Mastery domains showed larger
increases for placebo than for FP 500 \[clinstat\\copd\\sfca3006.pdf,
pages 2009-2045\].

Examination of the "reduced ITT population" revealed similar findings as
the ITT population, with the exception of the Fatigue domain which
showed a small clinically significant increase from baseline for SAL
50/FP 500. This change was not significantly different from the change
from baseline in the placebo group, however
\[clinstat\\copd\\sfca3006.pdf, pages 1128-1164\].

**Table 11.2.18. Chronic Respiratory Disease Questionnaire (CRDQ),
COPD-related quality of life instrument, ITT population, SFCA3006
\[clinstat\\copd\\sfca3006.pdf, pages 2009, 2027, 2045\].**

  --------------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ -------
                  **Pbo**                          **SAL 50**                       **FP 500**                       **SAL 50/FP              
                                                                                                                     500**                    

                  **Score**   **Mean       **n**   **Score**   **Mean       **n**   **Score**   **Mean       **n**   **Score**   **Mean       **n**
                              change from                      change from                      change from                      change from  
                              baseline**                       baseline**                       baseline**                       baseline**   

  **Overall                                                                                                                                   
  score\***                                                                                                                                   

  **Baseline**    86.2        NA           177     87.6        NA           157     88.5        NA           166     87.1        NA           163

  **Endpoint**    91.3        5.0          175     95.8        8.0          155     93.5        4.8          163     97.1        10.0         161

  **Physical                                                                                                                                  
  summary                                                                                                                                     
  score\*\***                                                                                                                                 

  **Baseline**    32.5        NA           177     33.4        NA           157     33.9        NA           166     33.5        NA           163

  **Endpoint**    35.2        2.7          175     38.1        4.6          155     37.4        3.4          163     39.6        6.1          161

  **Emotional                                                                                                                                 
  summary                                                                                                                                     
  score\*\*\***                                                                                                                               

  **Baseline**    53.8        NA           178     54.4        NA           159     54.7        NA           167     53.7        NA           164

  **Endpoint**    56.2        2.3          176     57.9        3.4          157     56.0        1.2          164     57.6        3.9          162
  --------------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ -------

\*Clinically significant change in Overall Score = 10.0 points

\*\*Clinically significant change in Physical Summary Score = 4.5 points

\*\*\*Clinically significant change in Emotional Summary Score = 5.5
points

*[Reviewer comment:]{.underline}*

*A clinically significant increase from baseline was observed in the
Overall score for SAL 50/FP 500 only. This increase was not clinically
significantly different from the increase from baseline for the placebo
group, however. In general, most of the individual domain and summary
scores also did not show clinically significant increases, and none were
clinically significantly different from the placebo group. As there was
no clinically significant difference from the placebo group in the
Overall score, any changes in individual domains or summary scores
provide little meaningful information. These data provide no additional
support for the efficacy of FP in this population.*

#### Smoking status, subgroup analysis

The sponsor provided an analysis of efficacy by patient smoking status.
Former smokers had the largest mean change from baseline in pre-dose
FEV~1~ at endpoint \[clinstat\\copd\\sfca3006.pdf, page 130\]. These
data are displayed in Table 11.2.19. Among the former smokers, those
treated with SAL 50/FP 500 had the largest change in FEV~1~ (179 mL),
followed by those treated with FP 500 (139 mL), SAL 50 (132 mL), and
with the smallest change in those treated with placebo (16 mL). Patients
who were smokers during the conduct of the study had smaller mean
changes from baseline in pre-dose FEV~1~, with the largest change in
patients treated with SAL 50/FP 500 (130 mL), and followed by SAL 50 (78
mL) and FP 500 (73 mL). The smallest change was in placebo patients (-21
mL).

Table 11.2.19. Mean change from baseline in pre-dose FEV~1~ at endpoint,
by smoking status \[clinstat\\copd\\sfca3006.pdf, page 130\].

+----------+--------------+--------------+--------------+--------------+
| *        | **Placebo**  | **SAL 50**   | **FP 500**   | **SAL 50/FP  |
| *Smoking |              |              |              | 500**        |
| status** | **Mean**     | **Mean**     | **Mean**     |              |
|          |              |              |              | **Mean**     |
|          | **Change, mL | **change, mL | **change, mL |              |
|          | (n)**        | (n)**        | (n)**        | **change, mL |
|          |              |              |              | (n)**        |
+==========+==============+==============+==============+==============+
| Current  | -21 (97)     | 78 (74)      | 73 (77)      | 130 (76)     |
| smokers  |              |              |              |              |
+----------+--------------+--------------+--------------+--------------+
| Former   | 16 (84)      | 132 (86)     | 139 (91)     | 179 (89)     |
| smokers  |              |              |              |              |
+----------+--------------+--------------+--------------+--------------+

The sponsor also examined other efficacy endpoints by patient smoking
status. As with FLTA3025, in general, where there were differences
between the groups, efficacy was favored in the former smokers. There
was little difference between the FP 500 group and the placebo group for
the change in baseline in the CBSQ GAS for both current and former
smokers. The TDI for FP 500 was similar for current and former smokers,
however, there was a larger increase in current smokers treated with
placebo. Current smokers treated with FP 500 had a lower percentage of
COPD exacerbations than former smokers treated with FP 500. Current
smokers treated with placebo had a higher percentage of COPD
exacerbations than former smokers treated with placebo. Changes in PEFRs
for patients treated with FP 500 were slightly higher in former smokers
than in current smokers, similar to the FEV~1~ data. There was no
clinically significant change in the Overall CRDQ score at endpoint in
the FP 500 group for former smokers or current smokers, and the degree
of change in these groups was no different than their respective placebo
groups \[clinstat\\copd\\sfca3006.pdf, page 165\].

*[Reviewer comment:]{.underline}*

*These data suggest that in general, efficacy favored patients who
stopped smoking prior to the conduct of the study.*

#### "Non-reversible" population, subgroup analysis

Assignment to study drug was to be stratified according to the patients'
response to reversibility testing with Ventolin at screening to a
non-reversible group and a reversible group. Non-reversible patients
were defined as having an absolute volume increase \<200 mL or an
absolute volume increase of ≥200 mL with baseline FEV~1~ reversibility
of \<12%. Reversible patients were defined as having an absolute volume
increase ≥200 mL with baseline FEV~1~ reversibility of ≥12%
\[clinstat\\copd\\sfca3006.pdf, page 11832; IND 44,090 N134 PN, 8/4/98,
page 25\]. Despite having assignment stratified based on
"non-reversibility," the sponsor did not initially include an analysis
for this subgroup. The sponsor was asked to provide a subgroup analysis
of the non-reversible group in an IR on 10/2/01. The sponsor submitted
this information in a document dated 1/17/01 \[NDA 20-833, SE1 004 BZ,
10/17/01\]. The results of the subgroup analysis for the non-reversible
population are briefly reviewed below.

Table 11.2.20 summarizes the mean change in FEV~1~ from baseline for the
"non-reversible" population. Increases from baseline in pre-dose FEV~1~
at endpoint were noted in all active treatment groups. The largest
increase was in the SAL 50/FP 500 group (116 mL), followed by FP 500 (93
mL), and SAL 50 (80 mL). The placebo group had a decrease from baseline
at endpoint (-8 mL) \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf,
pages 9, 196-201\].

A similar pattern was noted for mean change from baseline in pre-dose
FEV~1~ at Weeks 12 and 24. The largest increases were for the SAL 50/FP
500 group, followed by FP 500 and SAL 50 with similar degrees of change.
Decreases from baseline were noted at these visits for the placebo group
\[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, pages 9, 196-201\].

**Table 11.2.20. Mean change in pre-dose FEV~1~** from baseline, primary
efficacy variable, non-reversible population, SFCA3006 \[NDA 20-833 SE1
004, BZ, 10/17/01\\response.pdf, pages 9, 196-201\].

  -------------- ------------- --------- ------- --------- --------- ------- --------- --------- ------- --------- --------- -------
                 **Placebo**                     **SAL                       **FP                        **SAL               
                                                 50**                        500**                       50/FP               
                                                                                                         500**               

  **Study week** **Mean        **Mean    **n**   **Mean    **Mean    **n**   **Mean    **Mean    **n**   **Mean    **Mean    **n**
                 FEV~1~, mL**  change,           FEV~1~,   change,           FEV~1~,   change,           FEV~1~,   change,   
                               mL**              mL**      mL**              mL**      mL**              mL**      mL**      

  **Baseline**   1230          NA        80      1132      NA        78      1114      NA        78      1129      NA        77

  **Week 12**    1250          -16       52      1238      78        60      1191      66        54      1293      135       61

  **Week 24**    1254          -23       46      1306      76        48      1271      108       44      1283      110       48

  **Endpoint**   1238          -8        74      1220      80        77      1219      93        75      1256      116       73
  -------------- ------------- --------- ------- --------- --------- ------- --------- --------- ------- --------- --------- -------

Response of the reversible population in the mean change in FEV~1~ from
baseline is summarized in Table 11.2.21. The difference from placebo for
mean change from baseline at endpoint for the reversible group for FP
500 was 124 mL. This was 23% greater than the difference from placebo
for mean change from baseline at endpoint for the non-reversible group,
which for FP 500 was 101 mL \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, page 9\].

**Table 11.2.21. Mean change in pre-dose FEV~1~** from baseline, primary
efficacy variable, reversible population, SFCA3006 \[NDA 20-833 SE1 004,
BZ, 10/17/01\\response.pdf, pages 9, 202-207\].

  -------------- ------------- --------- ------- --------- --------- ------- --------- --------- ------- --------- --------- -------
                 **Placebo**                     **SAL                       **FP                        **SAL               
                                                 50**                        500**                       50/FP               
                                                                                                         500**               

  **Study week** **Mean        **Mean    **n**   **Mean    **Mean    **n**   **Mean    **Mean    **n**   **Mean    **Mean    **n**
                 FEV~1~, mL**  change,           FEV~1~,   change,           FEV~1~,   change,           FEV~1~,   change,   
                               mL**              mL**      mL**              mL**      mL**              mL**      mL**      

  **Baseline**   1322          NA        101     1250      NA        81      1228      NA        88      1366      NA        86

  **Week 12**    1393          -9        75      1426      136       71      1367      93        67      1566      231       71

  **Week 24**    1406          -14       66      1439      145       66      1436      150       55      1542      232       65

  **Endpoint**   1134          -1        97      1382      132       81      1367      123       86      1545      191       84
  -------------- ------------- --------- ------- --------- --------- ------- --------- --------- ------- --------- --------- -------

In general, secondary endpoints demonstrated small changes from baseline
for SAL 50, FP 500, and SAL 50/FP 500 in the non-reversible population.

Changes at endpoint from baseline in the GAS of the CBSQ were noted for
all treatment groups, but there were no clinically significant
differences from the placebo group \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, pages 10, 298\]. Changes at endpoint from
baseline in the TDI showed a clinically significant difference from
placebo for the SAL 50/FP 500 group, but not the SAL 50 or FP 500 groups
\[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, page 298\]. The
incidence and frequency of exacerbations due to COPD were similar across
the active and placebo treatment groups. The incidences and frequencies
of moderate/severe COPD exacerbations were similar across the active and
placebo treatment groups for this population \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, pages 11, 306, 308\].

*[Reviewer comment:]{.underline}*

*As noted earlier in this review, neither the CBSQ nor the TDI are
likely to provide useful information because of insufficient
validation.*

There was a slightly lower probability of first COPD exacerbation during
the first third of the study for the SAL 50/FP 500 group compared with
the other treatment groups. However, the probabilities for first COPD
exacerbation were similar for all treatment groups by the end of the
study \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, page 176\]. The
probabilities for first moderate to severe COPD exacerbation were
similar for all treatment groups throughout the entire duration of the
study \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, page 178\].

In general, small changes from baseline favoring SAL 50, FP 500, and SAL
50/ FP 500 were noted in for the non-reversible population for the
following secondary endpoints: AM PEFR, and number of puffs of Ventolin
used per day. In general, effects for these endpoints were greatest for
SAL 50/FP 500, followed by SAL 50, with FP 500 having the smallest
effect for these endpoints \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, pages 12, 329, 337\]. Awakenings per night
requiring Ventolin showed little difference between treatment groups
\[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, page 345\].

The overall score of the CRDQ, the health-related quality of life
instrument, showed a clinically significant increase from baseline at
endpoint for the SAL 50/FP 500 group. However this increase was not
clinically significantly different from the placebo group \[NDA 20-833
SE1 004, BZ, 10/17/01\\response.pdf, page 350\].

*[Reviewer comment:]{.underline}*

*This analysis of primary efficacy variable and selected secondary
variables in the non-reversible population provide some support for
efficacy of FP, in contrast to similar data in study FLTA 3025. The
reason for the discordance between this study and FLTA 3025 is unclear.*

#### Safety outcomes

Safety variables for this study included AEs, ECGs, hematology and
clinical chemistry studies, oropharyngeal examinations, and vital signs
\[clinstat\\copd\\sfca3006.pdf, pages 11844-11849\].

Cosyntropin (Cortrosyn) stimulation testing was performed at selected
study sites on Day 1 and Week 24 or Discontinuation
\[clinstat\\copd\\sfca3006.pdf, pages 11857-11858\].

Twenty-four hour Holter monitoring was to be conducted at approximately
14 study centers on approximately 160 patients
\[clinstat\\copd\\sfca3006.pdf, page 11845-11847\].

##### Total drug exposure

Total drug exposure is summarized in Table 11.2.22. Approximately 60% of
each group completed ≥24 weeks of study treatment. The mean duration of
treatment was 123.6 days for placebo, 141.1 days for SAL 50, 126.5 days
for FP 500, and 137.8 days for SAL 50/FP 500.

Table 11.2.22. Total drug exposure, SFCA3006
\[clinstat\\copd\\sfca3006.pdf, pages 172, 1380\].

+-------------+-------------+-------------+-------------+-------------+
| **Duration  | **Placebo** | **SAL 50**  | **FP 500**  | **SAL 50/FP |
| of          |             |             |             | 500**       |
| treatment** | **N = 185** | **N = 164** | **N = 173** |             |
|             |             |             |             | **N = 169** |
|             | **n (%)**   | **n (%)**   | **n (%)**   |             |
|             |             |             |             | **n (%)**   |
+=============+=============+=============+=============+=============+
| Any         | 185 (100)   | 164 (100)   | 173 (100)   | 169 (100)   |
| treatment   |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| ≥4 weeks    | 158 (85)    | 150 (92)    | 153 (88)    | 153 (90)    |
+-------------+-------------+-------------+-------------+-------------+
| ≥8 weeks    | 146 (79)    | 139 (80)    | 141 (82)    | 143 (85)    |
+-------------+-------------+-------------+-------------+-------------+
| ≥12 weeks   | 139 (75)    | 134 (82)    | 129 (75)    | 137 (81)    |
+-------------+-------------+-------------+-------------+-------------+
| ≥16 weeks   | 124 (67)    | 131 (80)    | 115 (66)    | 132 (78)    |
+-------------+-------------+-------------+-------------+-------------+
| ≥20 weeks   | 119 (64)    | 125 (76)    | 105 (61)    | 123 (73)    |
+-------------+-------------+-------------+-------------+-------------+
| ≥24 weeks   | 101 (55)    | 109 (66)    | 97 (56)     | 100 (59)    |
+-------------+-------------+-------------+-------------+-------------+
| Treatment   | 123.6       | 141.1       | 126.5       | 137.8       |
| days, mean  |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

*[Reviewer comment:]{.underline}*

*Drug exposure appears to be adequate to allow for assessment of
short-term safety, and noting the limitations that the design and
duration of this study impose, and recognizing that compliance reporting
is commonly unreliable. Compliance assessment was based on data from the
Diskus dose counter, which cannot accurately assess whether patients
actually received the drug that was dispensed.*

##### Cosyntropin stimulation testing

Cosyntropin (Cortrosyn) stimulation testing was performed at selected
study sites on Day 1 and Week 24 or Discontinuation
\[clinstat\\copd\\sfca3006.pdf, pages 11857-11858\]. Cosyntropin
stimulation was to be performed according to the package insert for
Cortosyn® \[clinstat\\copd\\sfca3006.pdf, pages 118549\]. The sponsor
used an HPLC assay for analysis of cortisol levels. The study report
states that the threshold values for interpretation of the cosyntropin
stimulation testing were adjusted downward from those in the package
insert for Cortrosyn® because the values in the package insert were
based on a less specific radioimmunoassay
\[clinstat\\copd\\sfca3006.pdf, page 90\]. The sponsor states that this
adjustment is consistent with previously published data^11,\ 12^.
Abnormalities for this test was defined as:

-   AM plasma cortisol \<4 mcg/dL

-   Peak post-stimulation cortisol \<14.5 mcg/dL

-   Change from baseline of \<5.6 mcg/dL

-   Peak post-stimulation cortisol \<14.5 mcg/dL and change from
    baseline of \<5.6 mcg/dL

There is no mention in the protocol of the type of assay that was to be
used for cortisol, or of the definitions for abnormalities in cortisol
levels.

*[Reviewer comment:]{.underline}*

*The definitions for abnormalities in cortisol levels with the
cosyntropin stimulation test are consistent with the sponsor's
references. It would have been preferable to specify in the protocol
both the assay to be used and the definitions of an abnormal test,
however.*

The number and percentage of patients with abnormalities in cosyntropin
stimulation testing is displayed in Table 11.2.23. The numbers of
patients with cortisols were incorrect in the initial submission, but
were corrected in a subsequent response NDA 20-833 SE1 004, BZ,
10/26/01\\response.pdf\]. The correct numbers are displayed in Table
1.2.23 and are reviewed in this section.

There were no differences between treatment groups in the percentage of
patients who had pre-stimulation AM cortisol levels \<4 mcg/dL at Day 1
and Endpoint. There was an increase in the percentage of patients with a
change in post-stimulation cortisol \<5.6 mcg/dL from Day 1 to Endpoint
for SAL 50 (11% to 14%), for FP 500 (5% to 16%), and SAL 50/FP 500 (10%
to 17%). There was no increase in the percentage of patients with a
change in post-stimulation cortisol \<5.6 mcg/dL for the placebo group
(7% to 5%). There was an increase in the percentage of patients with
post-stimulation cortisol levels \<14.5 mcg/dL from Day 1 to Endpoint
for the FP 500 group (3% to 8%) the SAL 50/FP 500 group (3% to 6%), and
the placebo group (2% to 8%). There was no increase in the percentage of
patients with post-stimulation cortisol levels \<14.5 mcg/dL from Day 1
to Endpoint for the SAL 50 group (5% to 3%).

Table 11.2.23. Number and percentage of patients with abnormalities in
cosyntropin stimulation testing, all patients with cortisol levels,
SFCA3006 \[clinstat\\copd\\sfca3006.pdf, pages 1464, 1467; NDA 20-833
SE1 004, BZ, 10/26/01\\response.pdf, page 6\].

+-------------+------+------+------+------+------+------+------+------+
|             | Day  |      |      |      | Endp |      |      |      |
|             | 1    |      |      |      | oint |      |      |      |
+=============+======+======+======+======+======+======+======+======+
|             | Pbo  | SAL  | FP   | SAL  | Pbo  | SAL  | FP   | SAL  |
|             |      | 50   | 500  | 50/  |      | 50   | 500  | 50/  |
|             | N    |      |      | FP   | N    |      |      | FP   |
|             | =185 | N    | N    | 500  | =185 | N    | N    | 500  |
|             |      | =164 | =173 |      |      | =164 | =173 |      |
|             | n    |      |      | N    | n    |      |      | N    |
|             | (%)  | n    | n    | =169 | (%)  | n    | n    | =169 |
|             |      | (%)  | (%)  |      |      | (%)  | (%)  |      |
|             |      |      |      | n    |      |      |      | n    |
|             |      |      |      | (%)  |      |      |      | (%)  |
+-------------+------+------+------+------+------+------+------+------+
| Patients    | 44   | 38   | 39   | 39   | 37   | 36   | 38   | 36   |
| with        | (    | (    | (    | (    | (    | (    | (    | (    |
| cortisol    | 100) | 100) | 100) | 100) | 100) | 100) | 100) | 100) |
| levels      |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| Pre-stim AM | 0    | 1    | 0    | 1    | 0    | 0    | 1    | 0    |
| cortisol    | (0)  | (3)  | (0)  | (3)  | (0)  | (0)  | (3)  | (0)  |
|             |      |      |      |      |      |      |      |      |
| \<4 mcg/dL  |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| Post-stim   | 3    | 4    | 2    | 4    | 2    | 5    | 6    | 6    |
| change      | (7)  | (11) | (5)  | (10) | (5)  | (14) | (16) | (17) |
|             |      |      |      |      |      |      |      |      |
| \<5.6       |      |      |      |      |      |      |      |      |
| mcg/dL      |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| Post-stim   | 1    | 2    | 1    | 1    | 3    | 1    | 3    | 2    |
| cortisol    | (2)  | (5)  | (3)  | (3)  | (8)  | (3)  | (8)  | (6)  |
|             |      |      |      |      |      |      |      |      |
| \<14.5      |      |      |      |      |      |      |      |      |
| mcg/dL      |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+

Mean cortisol levels for cosyntropin stimulation testing are displayed
in Table 11.2.24. Mean pre-stimulation cortisol levels were slightly
lower at Endpoint than at Day 1 for the SAL 50 group, FP 500 group, and
the SAL 50/FP 500 groups, but not the placebo group. Mean
post-stimulation cortisol levels were slightly lower for all treatment
groups at Endpoint than at Day 1. Mean post-stimulation cortisol levels
decreased the most for the FP 500 (24.01 mg/dL to 21.42 mg/dL) and SAL
50/FP 500 (24.71 mg/dL to 21.92 mg/dL) groups. A smaller decrease was
noted in the placebo (24.19 mg/dL to 23.61 mg/dL) and SAL 50 (24.12
mg/dL to 23.20 gm/dL) groups. A smaller rise in mean cortisol levels
were noted with cortisol stimulation at Endpoint for the FP 500 and SAL
50/FP 500 groups than for the SAL 50 and placebo groups.

Table 11.2.24. Mean cortisol levels, pre-and post-cosyntropin
stimulation, SFCA3006 \[clinstat\\copd\\sfca3006.pdf, pages 1462-1463\].

+----------+------+------+------+------+------+------+------+------+
|          | Day  |      |      |      | Endp |      |      |      |
|          | 1    |      |      |      | oint |      |      |      |
+----------+------+------+------+------+------+------+------+------+
|          | Pbo  | SAL  | FP   | SAL  | Pbo  | SAL  | FP   | SAL  |
|          |      | 50   | 500  | 50/  |      | 50   | 500  | 50/  |
|          | N    |      |      | FP   | N    |      |      | FP   |
|          | =185 | N    | N    | 500  | =185 | N    | N    | 500  |
|          |      | =164 | =173 |      |      | =164 | =173 |      |
|          |      |      |      | N    |      |      |      | N    |
|          |      |      |      | =169 |      |      |      | =169 |
+----------+------+------+------+------+------+------+------+------+
| Pre-sti  | 1    | 1    | 1    | 1    | 1    | 1    | 1    | 1    |
| mulation | 2.75 | 2.37 | 3.09 | 3.66 | 2.89 | 1.77 | 2.04 | 2.14 |
| c        |      |      |      |      |      |      |      |      |
| ortisol, | (5   | (4   | (4   | (6   | (5   | (4   | (5   | (5   |
| mcg/dL   | .30) | .93) | .89) | .65) | .13) | .29) | .08) | .34) |
|          |      |      |      |      |      |      |      |      |
| (SD)     |      |      |      |      |      |      |      |      |
+----------+------+------+------+------+------+------+------+------+
| Post-sti | 2    | 2    | 2    | 2    | 2    | 2    | 2    | 2    |
| mulation | 4.19 | 4.12 | 4.01 | 4.71 | 3.61 | 3.20 | 1.42 | 1.92 |
| c        |      |      |      |      |      |      |      |      |
| ortisol, | (5   | (5   | (5   | (6   | (6   | (4   | (5   | (5   |
| mcg/dL   | .28) | .35) | .20) | .51) | .79) | .95) | .22) | .94) |
|          |      |      |      |      |      |      |      |      |
| (SD)     |      |      |      |      |      |      |      |      |
+----------+------+------+------+------+------+------+------+------+
| Di       | 1    | 1    | 1    | 1    | 1    | 1    | 9.38 | 9.78 |
| fference | 1.44 | 1.75 | 0.92 | 1.05 | 0.72 | 1.43 |      |      |
| in       |      |      |      |      |      |      |      |      |
| means,   |      |      |      |      |      |      |      |      |
| pre-sti  |      |      |      |      |      |      |      |      |
| mulation |      |      |      |      |      |      |      |      |
| to       |      |      |      |      |      |      |      |      |
| po       |      |      |      |      |      |      |      |      |
| st-stimu |      |      |      |      |      |      |      |      |
| lation\* |      |      |      |      |      |      |      |      |
+----------+------+------+------+------+------+------+------+------+

\*Calculated from sponsor's data.

*[Reviewer comment:]{.underline}*

*Although there were small numbers of patients who had cosyntropin
stimulation testing, and fairly large standard deviations were noted,
there is a suggestion of a systemic corticosteroid effect in some
patients in the FP 500 and SAL 50/FP 500 groups for post-stimulation
change \<5.6 mcg/dL (Table 1.2.24). The larger decrease in mean
post-stimulation cortisol levels from Day to Endpoint for FP 500 and SAL
50/FP 500 is suggestive of a small systemic effect, as is the smaller
increase in mean cortisol levels in the FP 500 and SAL 50/FP 500 groups
at Endpoint. It should be noted that cosyntropin stimulation testing is
fairly insensitive, and the suggestion of a systemic effect in a small
number of patients is notable.*

##### 24-Hour Holter Monitoring

Twenty-four hour Holter monitoring was conducted at 18 study centers on
158 patients. Baseline monitoring was performed during the run-in period
at screening. Post-treatment monitoring was performed at Week 4.
Monitoring was to be started approximately 1 hour prior to
administration of the morning dose of study medication and continued for
24 hours \[clinstat\\copd\\sfca3006.pdf, pages 194-196, 11857-11858\].

The median numbers of ventricular and supraventricular events increased
from the screening visit for placebo, SAL 50, and FP 500 and decreased
in the SAL50/ FP 500. There was a fairly high range of variability in
the median number of ventricular and supraventricular events at the
screening visit \[clinstat\\copd\\sfca3006.pdf, page 195\].

Cardiac rates as determined by Holter monitoring were similar among
treatment groups at screening, and at Week 4. There was no significant
change from screening in cardiac rates as determined by Holter
monitoring at Week 4 \[clinstat\\copd\\sfca3006.pdf, pages 195,
1504-1507\].

There were five patients who had significant changes from screening in
the interpretation of Holter evaluations at Week 4. There was one FP 500
patient who experienced atrial fibrillation/flutter, one SAL 50/FP 500
who experienced heart block, and one patient each for placebo, FP 500,
and SAL 50 who experienced ventricular tachycardia.

*[Reviewer comment:]{.underline}*

*Holter monitoring results do not demonstrate significant differences
among treatment groups. The increase in median numbers of ventricular
and supraventricular events for placebo, SAL 50, and FP 500 are likely
to be due to the high range of variability noted, and not related to a
treatment effect.*

##### Adverse events

Adverse events (AEs) were common in this study. These data are
summarized in Table 11.2.25. AEs were more common in FP 500 (80%,
138/173) and SAL 50/FP 500 (78%, 131/169) patients than for placebo
(69%, 127/185). AEs occurring at a frequency ≥3% and more frequently
with FP 500 or SAL 50/FP 500 than with placebo included headaches, upper
respiratory tract infection, viral respiratory infection, candidiasis of
the mouth or throat, chest symptoms, sinusitis/sinus infection,
hypertension, hoarseness/dysphonia, dyspeptic symptoms, muscle pain, and
ear signs and symptoms. AEs coded as "chest symptoms" were reported as
chest pain, chest tightness, and chest discomfort
\[clinstat\\copd\\sfca3006.pdf, pages 5920-6667\]. Throat irritation,
upper respiratory inflammation, and muscle cramps and spasms were
reported at a frequency ≥3% and more frequently with SAL 50/FP 500 than
FP 250 and placebo.

Many of the AEs noted are noted in the labels for Flovent MDI and
Flovent Rotadisk. These include upper respiratory tract infection,
headaches, candidiasis, viral respiratory infections, nasal congestion,
dysphonia, and sinusitis. AEs reported in this study that are not noted
in current labeling for other Flovent products include muscle cramps,
spasms, and pain, chest symptoms (chest pain, chest tightness),
hypertension, dyspeptic symptoms, and ear signs and symptoms. Muscle
cramps, spasms, and pain may represent a new safety signal. It is
difficult to assess whether other AEs noted in this study that were not
noted in current Flovent labeling represent new safety signals because
of their low frequencies.

*[Reviewer comment:]{.underline}*

*There were many more patients with COPD exacerbations reported for the
secondary efficacy endpoint than were reported as AEs.*

Table 11.2.25. Adverse events occurring more frequently in FP 500 or SAL
50/FP 500 than in placebo and ≥3%, SCFA3006
\[clinstat\\copd\\sfca3006.pdf, page 174\].

+------------------------+--------------+--------------+--------------+
| **Adverse event**      | **Placebo**  | **FP 500**   | **SAL 50/FP  |
|                        |              |              | 500**        |
|                        | **N = 185**  | **N = 173**  |              |
|                        |              |              | **N = 169**  |
|                        | **n (%)**    | **n (%)**    |              |
|                        |              |              | **n (%)**    |
+========================+==============+==============+==============+
| All adverse events     | 127 (69)     | 138 (80)     | 131 (78)     |
+------------------------+--------------+--------------+--------------+
| Headaches              | 25 (14)      | 35 (20)      | 30 (18)      |
+------------------------+--------------+--------------+--------------+
| URTI                   | 18 (10)      | 25 (14)      | 28 (17)      |
+------------------------+--------------+--------------+--------------+
| Throat irritation      | 14 (8)       | 11 (6)       | 19 (11)      |
+------------------------+--------------+--------------+--------------+
| Upper respiratory      | 12 (6)       | 11 (6)       | 15 (9)       |
| inflammation           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Viral respiratory      | 6 (3)        | 17 (10)      | 14 (8)       |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Candidiasis            | 1 (\<1)      | 17 (10)      | 12 (7)       |
| mouth/throat           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Nasal                  | 7 (4)        | 13 (8)       | 7 (4)        |
| congestion/blockage    |              |              |              |
+------------------------+--------------+--------------+--------------+
| Muscle cramps and      | 4 (2)        | 3 (2)        | 13 (8)       |
| spasms                 |              |              |              |
+------------------------+--------------+--------------+--------------+
| Chest symptoms         | 6 (3)        | 7 (4)        | 6 (4)        |
+------------------------+--------------+--------------+--------------+
| Sinusitis/sinus        | 4 (2)        | 6 (3)        | 7 (4)        |
| infection              |              |              |              |
+------------------------+--------------+--------------+--------------+
| Hypertension           | 4 (2)        | 5 (3)        | 5 (3)        |
+------------------------+--------------+--------------+--------------+
| Hoarseness/dysphonia   | 4 (2)        | 9 (5)        | 5 (3)        |
+------------------------+--------------+--------------+--------------+
| Dyspeptic symptoms     | 1 (\<1)      | 5 (3)        | 4 (2)        |
+------------------------+--------------+--------------+--------------+
| COPD                   | 2 (1)        | 5 (3)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Muscle pain            | 1 (\<1)      | 5 (3)        | 7 (4)        |
+------------------------+--------------+--------------+--------------+
| Ear signs and symptoms | 2 (1)        | 3 (2)        | 4 (2)        |
+------------------------+--------------+--------------+--------------+

AEs beginning after a patient discontinued study medication were
infrequent and occurred at similar frequencies in active treatment
groups and placebo \[clinstat\\copd\\sfca3006.pdf, page 175\]. The
highest incidence of AEs was in the first month of treatment (45%
placebo, 45% FP 500, 47% SAL 50/FP 500). Throat irritation and
dysphonia/hoarseness tended to be more prevalent early in the study
\[clinstat\\copd\\sfca3006.pdf, pages 177, 2083-2125\]. The most
common-drug related AEs included candidiasis of the mouth or throat,
throat irritation, hoarseness/dysphonia, and headaches
\[clinstat\\copd\\sfca30006.pdf, page 176\].

A listing of AEs of low frequency is found in Table 11.2.26. This
listing includes AEs that have been associated with use of
corticosteroids, such as candidiasis, hoarseness/dysphonia, infection,
and AEs of low frequency that suggest an association with FP. There were
slightly higher frequencies of infections of various types in FP-treated
patients than in placebo-treated patients. Candidiasis and
hoarseness/dysphonia are known to be associated with the use of inhaled
corticosteroids. Dental and gum disorders of various types occurred
slightly more frequently in FP-treated patients, and may be suggestive
of a new safety signal. Few cases of osteoporosis, cataracts and ocular
pressure disorders were noted, however these AEs were not specifically
examined by bone densitometry or formal ophthalmologic examination. The
frequency of fractures was 2% (3/169) for SAL 50/FP 500, \<1% (1/173)
for FP 500, and \<1% (1/185) for placebo. Small numbers of other AEs
were observed without a strong association with FP 500 or SAL 50/FP 500
\[clinstat\\copd\\sfca3006.pdf, pages 1381-1404\].

Table 11.2.26. Selected adverse events of low frequency, SFCA3006
\[clinstat\\copd\\sfca3006.pdf, pages 1381-1404\].

+------------------------+--------------+--------------+--------------+
| **Adverse event**      | **Placebo**  | **FP 500**   | **SAL5 50/FP |
|                        |              |              | 500**        |
|                        | **N = 185**  | **N = 173**  |              |
|                        |              |              | **N = 169**  |
|                        | **n (%)**    | **n (%)**    |              |
|                        |              |              | **n (%)**    |
+========================+==============+==============+==============+
| All adverse events\*   | 127 (69)     | 138 (80)     | 131 (78)     |
+------------------------+--------------+--------------+--------------+
| Candidiasis            | 1 (\<1)      | 17 (10)      | 12 (7)       |
| mouth/throat           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Hoarseness/dysphonia   | 4 (2)        | 9 (5)        | 5 (3)        |
+------------------------+--------------+--------------+--------------+
| Hypertension           | 4 (2)        | 5 (3)        | 5 (3)        |
+------------------------+--------------+--------------+--------------+
| Urinary infections     | 3 (2)        | 4 (2)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Bronchitis             | 1 (\<1)      | 3 (2)        | 3 (2)        |
+------------------------+--------------+--------------+--------------+
| Pneumonia              | 1 (\<1)      | 3 (2)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Anxiety                | 2 (1)        | 2 (1)        | 5 (3)        |
+------------------------+--------------+--------------+--------------+
| Dental discomfort &    | 0 (0)        | 2 (1)        | 4 (2)        |
| pain                   |              |              |              |
+------------------------+--------------+--------------+--------------+
| Contusions and         | 1 (\<1)      | 2 (1)        | 1 (\<1)      |
| hematomas              |              |              |              |
+------------------------+--------------+--------------+--------------+
| Depressive disorders   | 3 (2)        | 2 (1)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Cataracts              | 1 (\<1)      | 2 (1)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Fractures              | 1 (\<1)      | 1 (\<1)      | 3 (2)        |
+------------------------+--------------+--------------+--------------+
| Muscle atrophy         | 0 (0)        | 1 (\<1)      | 1 (\<1)      |
| weakness & tiredness   |              |              |              |
+------------------------+--------------+--------------+--------------+
| Hyperglycemia          | 0 (0)        | 1 (\<1)      | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Weight gain            | 0 (0)        | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Bacterial respiratory  | 0 (0)        | 1 (\<1)      | 0 (0)        |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Fungal skin infections | 0 (0)        | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Agitation              | 1 (\<1)      | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Mood disorders         | 0 (0)        | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Ocular pressure        | 1 (\<1)      | 0 (0)        | 2 (1)        |
| disorders              |              |              |              |
+------------------------+--------------+--------------+--------------+
| Diabetes mellitus      | 1 (\<1)      | 0 (0)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Disorders of hard      | 0 (0)        | 0 (0)        | 1 (\<1)      |
| tissues of teeth       |              |              |              |
+------------------------+--------------+--------------+--------------+
| Dental & gum           | 0 (0)        | 0 (0)        | 1 (\<1)      |
| inflammation           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Gastrointestinal       | 1 (\<1)      | 0 (0)        | 1 (\<1)      |
| hemorrhage             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Fungal urinary         | 0 (0)        | 0 (0)        | 1 (\<1)      |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Fungal reproductive    | 1 (\<1)      | 0 (0)        | 1 (\<1)      |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Increased blood        | 0 (0)        | 0 (0)        | 1 (\<1)      |
| pressure               |              |              |              |
+------------------------+--------------+--------------+--------------+
| Fungal infections      | 0 (0)        | 0 (0)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Peptic ulcers          | 1 (\<1)      | 0 (0)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Osteoporosis           | 1 (\<1)      | 0 (0)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+

Subgroup analysis of AEs by gender, age, and race will be reviewed in
the Integrated Review of Safety section of this document.

*[Reviewer comment:]{.underline}*

*The relatively high frequency of oropharyngeal thrush in the groups
receiving FP is worth noting and may be indicative of a more globally
immunosuppressed condition. There were a few patients reported as having
"contusions and hematomas," and one patient was reported to have "skin
hemorrhage." Otherwise, there were no other patients who were reported
as having bruising or purpura. One would expect a fairly significant
number of patients to have had this AE, given the large doses of FP used
and given the older ages of the patients studied. Unfortunately this
study was not designed to specifically look for cataract or systemic
bone effects, both known to be associated with systemic effects of
corticosteroids. Ophthalmologic examination and studies to assess
osteoporosis would have been helpful to address these concerns.*

##### Deaths and serious adverse events

There were three patients who died during the conduct of the study. Each
of these patients was in the placebo group. There were no patients who
died who were treated with active drug. The three deaths in this study
are described below.

One patient, #10798, a 66-year old woman, developed severe abdominal
pain and was discovered to have adenocarcinoma of the small bowel. She
died approximately one month after onset of the pain. The second
patient, #11283, was a 60-year old male who was diagnosed as having
multiple colonic tumors, and after a subtotal colectomy, developed an
aspiration pneumonia and died. The third patient, #11379, was a 69-year
old male who was discovered to have recurrent thyroid cancer. This
patient had a surgical resection and tracheostomy, but did not receive
radiation or chemotherapy and died \[clinstat\\copd\\sfca3006.pdf, pages
178-179, 6667\].

There were 39 patients (39/691) who experienced a serious adverse event
(SAE) during the treatment phase of the study. The percentage of
patients was SAEs during the treatment phase were similar among the
treatment groups, with the highest in the FP 500 group (7%, 12/173),
followed by placebo (6%, 11/185), and SAL 50/FP 500 (5%, 9/169). SAEs
occurring in more than one patient are displayed in Table 11.2.27. SAEs
due to chronic obstructive airways disease were most frequent in FP 500
(3%, 6/173) compared with placebo (1%, 2/185) and SAL 50/FP 500 (1%,
2/169). SAEs for pneumonias occurred only in FP 500 (1%, 2/173) and SAL
50/FP 500 (1%, 2/169). Chest symptoms (literal term "chest pain")
occurred in equal frequencies for placebo (1%, 2/185) and in SAL 50/FP
500 (1%, 2/169).

Table 11.2.27. SAEs occurring in more than one patient during the
treatment period, SFCA3006 \[clinstat\\copd\\sfca3006.pdf, pages
252-253, 1411-1413\].

+------------------------+--------------+--------------+--------------+
| **Serious adverse      | **Placebo**  | **FP 500**   | **SAL 50/FP  |
| event**                |              |              | 500**        |
|                        | **N = 185**  | **N = 173**  |              |
|                        |              |              | **N = 169**  |
|                        | **n (%)**    | **n (%)**    |              |
|                        |              |              | **n (%)**    |
+========================+==============+==============+==============+
| Any serious adverse    | 11 (6)       | 12 (7)       | 9 (5)        |
| event                  |              |              |              |
+------------------------+--------------+--------------+--------------+
| Chronic obstructive    | 2 (1)        | 6 (3)        | 2 (1)        |
| airways disease\*      |              |              |              |
+------------------------+--------------+--------------+--------------+
| Pneumonia              | 0 (0)        | 2 (1)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Chest symptoms\*\*     | 2 (1)        | 0 (0)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+

\*Includes one FP 500 patient (#10931) with respiratory failure due to
COPD exacerbation that was coded as "respiratory failure."

\*\*All events coded as chest symptoms were due to chest pain.

There was one patient in the FP 500 group that had a SAE for fracture.
This patient, #11029, was a 69-year old male who was involved in a motor
vehicle accident and sustained a concussion and fracture of C1 and C2
vertebrae, but sustained no spinal cord damage
\[clinstat\\copd\\sfca3006.pdf, page 289\]. There were no other SAEs for
fracture.

*[Reviewer comment:]{.underline}*

*The higher frequency of SAEs for COPD and pneumonia in the FP 500 and
SAL 50/FP 500 groups than in the placebo group is interesting. As noted
earlier in this review, AEs for bronchitis and pneumonia were more also
more common in FP 500 and SAL 50/FP 500 than in placebo. Although there
was a fairly small number of patients with these SAEs, it is possible
that this may suggest a higher risk of infection or exacerbation of COPD
for FP 500 and SAL 50/FP 500.*

##### Withdrawals due to adverse events

Withdrawals due to adverse events (AEs) are displayed in Table 11.2.28.
Withdrawals due to AEs were most common in the FP 500 group (12%,
20/173), followed by the placebo group (8%, 15/185) and the SAL 50/FP
500 groups (7%, 11/169). Withdrawals due to COPD were most common in the
FP 500 group 3%, 6/173), followed by the placebo group (1%, 2/185) and
the SAL 50/FP 500 group (1%, 2/169). Withdrawals due to pneumonia were
more common in FP 500 (1%, 2/173) and SAL 50/FP 500 (1%, 2/169), than in
the placebo group (\<1%, 1/185). Candidiasis of the mouth and throat and
hoarseness/dysphonia, both known to be associated with the use of
inhaled corticosteroids, were most common in the FP 500 group.

Table 11.2.28. Withdrawals due to adverse events occurring in more than
one patient, SFCA3006 \[clinstat\\copd\\sfca3006.pdf, page 181\].

+------------------------+--------------+--------------+--------------+
| **Adverse event**      | **Placebo**  | **FP 500**   | **SAL 50/FP  |
|                        |              |              | 500**        |
|                        | **N = 185**  | **N = 173**  |              |
|                        |              |              | **N = 169**  |
|                        | **n (%)**    | **n (%)**    |              |
|                        |              |              | **n (%)**    |
+========================+==============+==============+==============+
| Any adverse event      | 15 (8)       | 20 (12)      | 11 (7)       |
+------------------------+--------------+--------------+--------------+
| Chronic obstructive    | 2 (1)        | 6 (3)        | 2 (1)        |
| airways disease\*      |              |              |              |
+------------------------+--------------+--------------+--------------+
| Pneumonia              | 1 (\<1)      | 2 (1)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Candidiasis            | 0 (0)        | 2 (1)        | 0 (0)        |
| mouth/throat           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Hoarseness/dysphonia   | 1 (\<1)      | 2 (1)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Chest symptoms\*\*     | 1 (\<1)      | 0 (0)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Malaise and fatigue    | 2 (1)        | 0 (0)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Headaches              | 2 (1)        | 0 (0)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+

\*Includes one FP 500 patient (#10931) with respiratory failure due to
COPD exacerbation that was coded as "respiratory failure."

\*\*All events coded as chest symptoms were due to chest pain.

*[Reviewer comment:]{.underline}*

*As with AEs and SAEs, withdrawals due to pneumonia were more common for
FP 500 and SAL 50/FP 500 than for placebo. Withdrawals due to COPD were
most common in the FP 500 group, with similar frequencies in placebo and
SAL 50/FP 500.*

##### Vital signs

There were no clinically significant changes from baseline in median
values of vital signs for any of the treatment groups
\[clinstat\\copd\\sfca3006.pdf, pages 1521-1520\].

##### Physical examination

Physical examinations were performed at Screening and at the end of the
study \[clinstat\\copd\\sfca3006.pdf, page 74\]. Data was recorded on
subject progress notes, but not on case report forms (CRFs). Physical
examination abnormalities were recorded as AEs on the CRFs, but no
summary of physical examinations was provided \[NDA 20-833, SE1-004, BM,
9/17/01, page 3\].

##### Oropharyngeal examination

Oropharyngeal examinations were performed at the screening visit, at
each treatment visit and at the end of the study
\[clinstat\\copd\\sfca3006.pdf, page 74\]. Data was recorded on subject
progress notes, but not on case report forms (CRFs). Oropharyngeal
examination abnormalities were recorded as AEs on the CRFs, but no
summary of oropharyngeal examinations was provided \[NDA 20-833,
SE1-004, BM, 9/17/01, page 2\].

##### Laboratory studies

Small numbers of patients had shifts in % lymphocyte, % neutrophils, and
WBC counts from baseline at Weeks 12 and 24 and Discontinuation.

There was a decrease in % lymphocytes in patients treated with FP 500
(6%, 7/119) and SAL 50/FP 500 (4%, 5/130), but not placebo (\<1%, 1/131)
at week 12. The frequency of low % lymphocytes were similar among
treatment groups at Week 24 and at endpoint
\[clinstat\\copd\\sfca3006.pdf, pages 182, 1420-1430\].

Shifts in % neutrophils and WBC were similar among treatment groups at
Week 12, Week 24, and Discontinuation \[clinstat\\copd\\sfca3006.pdf,
pages 182, 1420-1430\].

There was a greater percentage of patients who had increases from
baseline in glucose at Discontinuation for FP 500 (9%, 5/58) and SAL
50/FP 500 (13%, 6/47) than with placebo (5%, 3/58). There was no
meaningful difference in the percentage of patients who had increases
from baseline in glucose at Week 12 between FP 500 (3%, 4/122), SAL
50/FP 500 (5%, 7/131), and placebo (8%, 11/131). There was no meaningful
difference in the percentage of patients who had increases from baseline
in glucose at Week 24 for FP 500 (6%, 6/98), SAL 50/FP 500 (6%, 6/98),
and placebo (7%, 8/111) \[clinstat\\copd\\sfca3006.pdf, pages 182,
1420-1430\]. It should be noted that the sponsor defined an
exceptionally liberal definition for high glucose, \>175 mg/ml. It is
likely that this liberal definition of high glucose would decrease the
sensitivity of detecting a difference between treatment groups for this
laboratory test \[clinstat\\copd\\sfca3006.pdf, page 6720\].

There were no meaningful differences among treatment groups in the
percentage of patients with changes in other laboratory studies
\[clinstat\\copd\\sfca3006.pdf, pages 182, 1420-1430\].

*[Reviewer comment:]{.underline}*

*Lympholysis is associated with systemic effects of corticosteroids. The
higher percentage of patients with decrease in % lymphocytes in FP 500
and SAL 50/FP 500 at Week 12 could be a manifestation of a systemic
corticosteroid effect. This effect was not noted at Week 24 and at
Discontinuation, perhaps due to dropouts. This may be a manifestation of
systemic corticosteroid activity. The higher percentage of patients with
increases from baseline in glucose at discontinuation could also be a
manifestation of a systemic corticosteroid effect. This effect was not
noted at Week 12 or Week 24. It is possible that this signal would have
been stronger if the sponsor had not chosen such a liberal definition of
elevated blood glucose.*

There were few patients with hematology or chemistry results outside of
values specified as normal by the sponsor. The few patients with results
outside of the range specified as normal by the sponsor were evenly
distributed between treatment groups \[clinstat\\copd\\sfca3006.pdf,
pages 1440-1461\].

##### ECGs

There were a few clinically significant changes in ECGs from baseline
for each of the treatment groups in the study. Patients with clinically
significant changes in ECGs are summarized in Table 11.2.29. There was
no significant difference between treatment groups in the number or
character of the changes in ECGs.

Table 11.2.29. Patients with clinically significant changes in ECGs from
baseline, SFCA3006 \[clinstat\\copd\\sfca3006.pdf, pages 188, 191,
1474-1485\].

  -----------------------------------------------------------------------------
  **Patient      **Treatment**   **Time of         **ECG abnormality**
  number**                       abnormality**     
  -------------- --------------- ----------------- ----------------------------
  11343          Placebo         Discontinuation   Subendocardial ischemia

  11384          Placebo         Week 12           P mitrale

  9250           FP 500          Discontinuation   Sinus tachycardia,
                                                   repolarization abnormalities

  9846           SAL 50/FP 500   Discontinuation   Nodal tachycardia

  10588          SAL 50/FP 500   Week 12           Atrial flutter
  -----------------------------------------------------------------------------

Median QTc intervals by both Bazette and Fridericia formulae were
similar for each of the treatment groups \[clinstat\\copd\\sfca3006.pdf,
pages 190-191, 1486-1493\]. Two patients with QTcB greater than 470 msec
were treated with FP 500, and six were treated with SAL 50/FP 500. These
patients are summarized in Table 11.2.30.

Table 11.2.30. Patients with QTcB intervals \>470 msec post-screening,
SCFA3006 \[clinstat\\copd\\sfca3006.pdf, pages 9181-9185\]

+-------------+-------------+-------------+-------------+-------------+
| **Patient   | **          | **Screening | **Week 12   | **Week 24   |
| number**    | Treatment** | QTcB,**     | QTcB,**     | or DC QTcB, |
|             |             |             |             | msec**      |
|             |             | **msec**    | **msec**    |             |
+=============+=============+=============+=============+=============+
| 11539       | FP 500      | 456.8       | 480.8       | 454.4       |
+-------------+-------------+-------------+-------------+-------------+
| 9711        | FP 500      | 488.0       | NA          | 480.7       |
+-------------+-------------+-------------+-------------+-------------+
| 10185       | SAL 50/FP   | 493.3       | 485.6       | 482.4       |
|             | 500         |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| 10237       | SAL 50/FP   | 463.8       | 517.7       | 488.6       |
|             | 500         |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| 10730       | SAL 50/FP   | 440.0       | 458.0       | 471.4       |
|             | 500         |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| 11128       | SAL 50/FP   | 481.7       | 481.7       | 511.8       |
|             | 500         |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| 15878       | SAL 50/FP   | 459.6       | 484.4       | 458.0       |
|             | 500         |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| 9691        | SAL 50/FP   | 406.6       | 499.9       | 420.1       |
|             | 500         |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

*[Reviewer comment:]{.underline}*

*There was a higher incidence of patients with QTcB \>470 post-screening
in the FP 500 and SAL50/FP 500 groups than in the placebo group. These
findings were present in only small number of patients, however, and
could be a chance occurrence.*

### References

1.  American Thoracic Society. Standards for the diagnosis and care of
    patients with chronic obstructive pulmonary disease. Am J Respir
    Crit Care Med 1995;152:S77-S121.

2.  Anthonisen NR, Wright EC, et al. Bronchodilator response in chronic
    obstructive pulmonary disease. Am Rev Respir Dis 1986;133: 814-819.

3.  Barnes PJ. Chronic Obstructive Pulmonary Disease. New Engl J Med
    2000;343:269-280.

4.  Eliasson O and Degraff AC. The Use of Criteria for Reversibility and
    Obstruction to Define patient Groups for Bronchodilator Trials. Am
    Rev Respir Dis 1985;132:858-864.

5.  National Asthma Education and Prevention Program. Expert Panel
    Report 2: Guidelines for the Diagnosis and Management of Asthma.
    National Institutes of Health Publication Number 97-4051. Bethesda,
    MD, 1997.

6.  Petty TL. The national mucolytic study: Results of a randomized,
    double-blind, placebo-controlled study of iodinated glycerol in
    chronic obstructive bronchitis. Chest 1990;97:75-83.

7.  Rubin BK, Ramirez O, Ohar JA. Iodinated glycerol has no effect on
    pulmonary function, symptom score, or sputum properties in patients
    with stable chronic bronchitis. Chest 1996;109:348-352.

8.  Mahler DA, Weinberg DH, et. al. The measurement of dyspnea.
    Contents, interobserver agreement, and physiologic correlates of two
    new clinical indexes. Chest 1984;97:751-758.

9.  Anthionisen NR, Manfreda J, Warren CPW, et. al. Antibiotic therapy
    in exacerbations of chronic obstructive pulmonary disease. Ann Int
    Med 1987;106:196-204.

10. Guyatt GH, Berman LB, Townsend M, et. al. A measure of quality of
    life for clinical trials in chronic lung diseases. Thorax
    1987;42:773-778.

11. Pulmicort package insert. Astra Inc., USA. Westborough, MA October
    1998.

12. Scott MB, Skoner DP. Short term and long term safety of budesonide
    inhalation suspension in infants and young children with persistent
    asthma. J Allergy Clin Immunol 1999;104: S200-209.

##   {#section-2 .unnumbered}

## SFCA3007: A randomized, double-blind, parallel-group trial of evaluating the safety and efficacy of the Diskus formulations of Salmeterol 50 mcg BID and fluticasone propionate 250 mcg BID individually and in combination as compared to placebo in COPD subjects

> Study initiated: 11/10/98
>
> Study completed: 8/2800
>
> Study report dated: 3/21/01

\[clinstat\\copd\\sfca3007.pdf, page 1\]

### Summary and reviewer\'s conclusion of study results

This was a randomized, double-blind, placebo-controlled, parallel group,
multicenter trial designed to evaluate the efficacy and safety of
salmeterol xinafoate (SAL) 50 mcg BID, fluticasone propionate FP 250 mcg
BID, the combination of SAL 50 mcg /FP 250 mcg BID, and placebo in
patients with chronic obstructive pulmonary disease (COPD).

As with studies FLTA3025 and SFCA3006, the proportion of patients with
reversibility enrolled in this study is much higher than is found in the
population of COPD patients at large^1-4^. Of all study patients, there
were 55% of patients in this study who were considered to be reversible
(≥12% and ≥200 mL increase in FEV~1~ with bronchodilator). In addition,
the degree of reversibility for the reversible population was
high---29.8%. The mean degree of reversibility in the 45% of the
patients who comprised the "non-reversible" population, 8.6%, was
similar to the mean reversibility described in studies of the COPD
population as a whole^1-4^, as broadly stated in the labeling for the
proposed indication. This is a critical deficiency of this study.
Non-Caucasian patients, who make up a substantial proportion of the COPD
population^1,\ 3^, were also under-represented in this study.

The primary efficacy endpoint was the mean change in FEV~1~ from
baseline to study endpoint. The primary efficacy endpoint supports the
efficacy of FP 250 compared to placebo in this population. The mean
change from baseline in FEV~1~ for the FP 250 group at endpoint was 109
mL, 108 mL more than the placebo group at endpoint. This comparison was
statistically significant at p \<0.001. This change corresponds to an
effect size of 8.7%.

Small decreases in the Chronic Bronchitis Symptom Questionnaire (CBSQ)
were noted for all active treatment groups at Weeks 1 to 24 and at
endpoint. In general, decreases were numerically superior to the placebo
group, which also showed an improvement in score. Decreases in the CBSQ
were not clinically significantly different from the placebo group for
any of the active treatment groups at any time, however. The differences
between the Transitional Dyspnea Indices (TDIs) for FP 250 and placebo
were not greater than the minimally clinically significant TDI of 1.0
point at Endpoint, or at any of the 10 interim measurements from Weeks 1
to 24. Neither the CBSQ nor the TDI provide support for the efficacy of
FP in COPD.

The incidence of COPD exacerbation and moderate to severe COPD
exacerbation was slightly higher for FP 250 than for the other treatment
groups. The proportion of patients who withdrew from the study, and
withdrawals due to COPD exacerbation were similar across treatment
groups. A non-standard definition of COPD exacerbation was used that
would have favored the finding of efficacy of FP in a COPD population
with a high degree of reversibility. As a general statement, incidence
or severity of COPD exacerbations did not provide support for the
efficacy of FP in COPD.

A small mean increase from baseline in AM PEFR was noted in FP 250 (11.3
L/min) and SAL 50 (14.7 L/min) groups at the end of the study. A larger
mean increase was observed in the SAL 50/FP 500 group (30.6 L/min).
Overall, the SAL 50 and SAL 50/FP 250 groups had small decreases in the
number of puffs of Ventolin used per day. The FP 250 and placebo groups
had little change in the number of puffs of Ventolin used per day.

All active treatment groups had small increases in the percent of days
without Ventolin use compared with placebo. Overall, the FP 250, SAL 50,
and SAL 50/FP 250 groups had very small decreases from baseline in the
number of awakenings per night and small increases in the percent of
nights with no awakenings requiring Ventolin use. Of the active
treatment groups, the FP 250 group had the smallest decrease number of
awakenings per night requiring Ventolin and the smallest increase in
percent of nights with no awakenings.

Increases in the Overall score of the Chronic Respiratory Disease
Questionnaire (CRDQ), a health-related quality of life instrument, were
less than the specified clinically significant difference from the
change in baseline in the placebo, and provide no support for efficacy.
This is an important negative finding, since one of the stated
objectives of this study was to compare the health-related quality of
life in COPD patients receiving active treatment compared to placebo
over this 24-week study.

The sponsor provided an analysis of efficacy by smoking status. In
general, efficacy was favored for the FP 250 and SAL 50/FP 250 groups in
patients who stopped smoking prior to the conduct of the study, compared
with patients who continued to smoke during the study.

The sponsor performed a subgroup analysis of efficacy for non-reversible
patients. This subgroup analysis demonstrated numerically greater
changes in FEV~1~ from baseline at study endpoint for all active
treatments compared with placebo. The difference from placebo for mean
change from baseline at endpoint for the reversible group for FP 250 was
153 mL. This was 98 mL greater than the difference from placebo for mean
change from baseline at endpoint for the non-reversible group, which for
FP 250 was 55 mL. Secondary endpoints provide no support for the
efficacy of FP 250 in non-reversible population.

Data for cosyntropin stimulation testing show no evidence of HPA-axis
suppression for FP 250 or SAL 50/FP 250. Duration of exposure was
inadequate to fully assess safety, since the short efficacy endpoints in
this study fail to address the safety consequences of long-term (\>6
months) use of high-dose, high-potency inhaled corticosteroids,
particularly with regard to bone, dermatological, and ocular adverse
events, was well as the potential for HPA axis recovery. AEs occurred in
70% of FP 250-treated patients, 70% of SAL 50/FP 250-treated patients,
and in 64% of placebo-treated patients. AEs occurring more frequently
with FP 500 and SAL 50/FP 500 than with placebo included headaches,
musculoskeletal pain, sinusitis, throat irritation, candidiasis of the
mouth/throat, viral respiratory infection, upper respiratory tract
inflammation, ear signs and symptoms, chest symptoms, sinusitis/sinus
infection, muscle injuries, hoarseness/dysphonia, fever, muscle cramps
and spasms, pain, epistaxis, edema and swelling, dizziness, nasal
congestion/blockage, and constipation. There were no deaths in this
study. The percentage of patients was SAEs during the treatment phase
was similar among the treatment groups, with the highest in the placebo
group (6%, 11/185), followed by FP 250 (5%, 10/183), and SAL 50/FP 500
(4%, 8/178). Withdrawals due to AEs occurred at similar frequencies
among treatment groups. Vital signs and ECGs showed no clinically
significant differences between treatment groups.

In summary, based on the primary endpoint, efficacy was demonstrated for
the FP 250 group in this study. An open issue is whether the study
population adequately reflects the overall population of US COPD
patients, although both the reversible and the non-reversible subgroups
showed some change from baseline for this endpoint. Subgroup analysis
demonstrated a numerically greater effect in the reversible compared to
the non-reversible population. Efficacy measurements that supported FP
250 included FEV~1~, and PEFR. Other measures of bronchodilator use and
COPD exacerbations did not support the efficacy of FP 250. The
health-related quality of life instrument (CRQD), the Transitional
Dyspnea Index (TDI), and the Chronic Bronchitis Symptom Questionnaire
(CBSQ) provided no support for the efficacy of FP 250. Data for the
safety endpoints chosen for this study are generally inadequate to make
a determination of the long-term safety of FP in the population studied
because the study was of insufficient duration for known systemic
corticosteroid effects such as osteoporosis, cataracts, hypertension,
diabetes, or skin changes such as easy bruisability or skin thinning to
become apparent. It should be noted that the study was not designed to
specifically assess these AEs, and patients with prior pathological
fracture, osteoporosis, significant hypertension, or diabetes,
cataracts, or glaucoma were specifically excluded. Although not
specifically addressed in this document (see review by Dr. L.
Gilbert-McClain), the safety issue of long-term systemic corticosteroid
effects will be similar for SAL 50/FP 500 (Advair®) in this population.

### Study design

This was a randomized, double-blind, placebo-controlled, parallel group,
multicenter trial. Approximately 600 patients were to be randomized at
approximately 55 study centers. A total of 723 patients were enrolled at
76 study sites \[clinstat\\copdsfca3007.pdf, pages 80, 7105\].

### Objectives

This study had three objectives \[clinstat\\copd\\sfca3007.pdf, pages
37, 7104\]. They were:

1.  To compare the efficacy of SAL 50 mcg BID, FP 250 mcg BID, the
    combination of SAL 50 mcg /FP 250 mcg BID, and placebo when
    administered by the Diskus over a 24-week treatment period in the
    treatment of COPD patients

2.  To compare the safety of SAL 50 mcg BID, FP 250 mcg BID, the
    combination of SAL 50 mcg /FP 250 mcg BID, and placebo when
    administered by the Diskus over a 24-week treatment period in the
    treatment of COPD patients

3.  To compare quality of life (QOL) in COPD patients receiving FSAL 50
    mcg BID, FP 500 mcg BID, the combination of SAL 50 mcg/FP 250 mcg
    BID, and placebo when administered by the Diskus over a 24-week
    treatment period

### Inclusion criteria

Inclusion criteria for this study are listed below. These reflect
protocol amendments. \[clinstat\\copd\\sfca3007.pdf, pages 7105-7108\]:

1.  Age ≥40 years

2.  Male or female gender

-   A female was eligible to enter and participate if she was of
    non-childbearing potential or was of child-bearing potential with a
    negative serum pregnancy test at screening and an acceptable method
    of contraception

3.  Established history of COPD in accordance with the American Thoracic
    Society (ATS) definition^1^:

-   Abnormal tests of expiratory flow that do not change markedly over
    periods of several months

```{=html}
<!-- -->
```
-   Airflow obstruction may be structural or functional

```{=html}
<!-- -->
```
-   Bronchial hyperreactivity may be present as measured by improvement
    after inhalation of a beta-adrenergic agent or worsening after
    inhalation of methacholine or histamine

```{=html}
<!-- -->
```
-   Emphysema and chronic bronchitis are incorporated into COPD, and any
    individual may have one or both of these conditions

4.  A history of cough productive of sputum on most days for at least 3
    months of the year, for at least 2 years, that is not attributed to
    another disease process. Patients must have a score of ≥4 on the
    Chronic Bronchitis Symptom Questionnaire (CBSQ) at Treatment Day 1

5.  Current or prior history of at least 20 pack-years of cigarette
    smoking. If the patient is an ex-smoker, smoking must have been
    discontinued for at least 6 months prior to screening. Current
    smokers were counseled regarding the hazards of continuing to smoke
    and the benefits of discontinuation. Patient who decided to stop
    smoking at the Screening Visit were not eligible for participation
    in the study. Patients making a conscious decision to stop smoking
    at anytime during the study and who refrain from smoking for \>4
    weeks were to be discontinued from the study. Patients who start
    smoking during the study and smoke for at least 7 consecutive days
    were to be discontinued from the study.

6.  Severity

-   Baseline FEV~1~ \<65% or predicted but \>0.70 L, or FEV~1~ \<0.70 L
    and \>40% but still \<65% of the predicted normal value (Crapo), and

```{=html}
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```
-   FEV~1~/FVC ratio of ≤70% at screening

7.  A score if ≥2 in the Modified Medical Research Council Dyspnea Scale
    at screening:

Modified Medical Research Council Dyspnea
Scale\[clinstat\\copd\\sfca3007.pdf, page 7154\]

  ----------- ---------------------------------------------------------------
  **Grade**   **Description**

  0           Not troubled with breathlessness except with strenuous exercise

  1           Troubled by shortness of breath when hurrying on the level or
              walking up a slight hill

  2           Walks slower than people of the same age on the level because
              of breathlessness or has to stop for breath when walking at own
              pace on the level

  3           Stops to breathe after walking about 100 yards or after a few
              minutes on the level

  4           Too breathless to leave the house or breathless when dressing
              or undressing
  ----------- ---------------------------------------------------------------

8.  Has not received systemic corticosteroid and/or high-dose inhaled
    corticosteroid therapy for at least 6 weeks prior to the Screening
    Visit. High dose inhaled corticosteroids are defined as:

-   Beclomethasone dipropionate ≥1008 mcg/day

-   Triamcinolone acetonide ≥1600 mcg/day

-   Flunisolide ≥2000 mcg/day

-   Fluticasone propionate MDI ≥880 mcg/day

-   Fluticasone propionate Diskus ≥1000 mcg/day

-   Budesonide ≥1600 mcg/day

9.  Able to tolerate a 2-week run-in period during which the following
    medications were discontinued:

-   Inhaled corticosteroids

-   Ipratropium

-   Nedocromil sodium and cromolyn sodium

-   Anti-leukotriene agents

-   Intranasal steroids

-   Any beta-agonist other than Ventolin

-   Theophylline, unless at a stable dosage for 14 days

10. Able to complete a diary card and subject questionnaires

11. Able to effectively use the Diskus and MDI inhalers, spirometry
    equipment, and mini-Wright peak flow meter

12. Provide a signed, dated, and witnessed informed consent

*[Reviewer comment:]{.underline}*

*The sponsor's paraphrase of the ATS definition of COPD places an
emphasis on reversibility. While reversible obstruction does occur in
the COPD population, it should not be considered central to the
definition. The process underlying COPD is one of progressive loss of
lung tissue, leading primarily to structural obstruction as opposed to
functional ^1^. The ATS definition follows:*

> *"COPD is defined 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."^1^*

*The inclusion criteria allow for patients who were receiving fairly
large doses of inhaled corticosteroids prior to enrollment. This may
have the effect of enriching the study for patients who were responsive
to inhaled corticosteroids, as one would expect patients with no
response or a poor response to have their treatment discontinued.*

### Exclusion criteria

Exclusion criteria for this study are listed below. These reflect
protocol amendments. \[clinstat\\copd\\sfca3007.pdf, pages 7108-7111\]:

1.  Current diagnosis of asthma in accordance with the ATS definition:

-   Increased responsiveness of the tracheobronchial tree

-   Paroxysms of dyspnea, wheezing, and cough, which may vary from mild
    and almost undetectable to severe and unremitting

-   Primary physiological manifestation of hyperresponsiveness is
    variable airway obstruction

-   Variability may be manifest in improvements of obstruction following
    bronchodilators or corticosteroids or increased obstruction caused
    by drugs or other stimuli

2.  Requirement for any of the following medications:

-   Beta-blockers

-   Digitalis

-   Ketoconazole, fluconazole

-   Monoamine oxidase inhibitors

-   Tricyclic antidepressants

-   Phenothiazines

-   Immunosuppressive agents including cyclosporine, methotrexate, and
    gold

-   Use of inhaled short-acting bronchodilator within 6 hours prior to
    screening

-   Use of any short acting form of oral beta-agonist, short-acting form
    of theophylline or other bronchodilator within 12 hours prior to
    screening

-   Use of any twice daily form of an inhaled or oral beta-agonist or
    controlled-release form of theophylline within 48 hours of screening

3.  Requirement for pulmonary rehabilitation that is initiated during
    the study. Participation in a maintenance pulmonary rehabilitation
    program was allowed.

4.  A respiratory disorder other than COPD (e.g., lung cancer,
    bronchiectasis, sarcoidosis, tuberculosis, lung fibrosis), history
    of lobectomy within one year of the screening visit. Patients with
    alpha-1-antitrypsin deficiency were excluded.

5.  Requirement for a continuous positive pressure device for COPD or
    sleep apnea.

6.  Any significant concurrent diseases that would place the subject at
    risk, interfere with clinical evaluations, or influence study
    participation, including but not limited to:

-   History of symptomatic or clinically significant pathologic
    fractures

-   Clinically significant cardiac disease

-   Systemic arterial hypertension if the subject is poorly compliant
    with medications, likely to require frequent changes in medication
    during the study period, or requires therapy with beta-blockers

```{=html}
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```
-   Hepatic disease

-   Renal disease requiring dialysis or at risk of requiring dialysis
    within 6 months of screening

-   Neurologic disease

-   Uncontrolled hyperthyroidism or hypothyroidism

-   Diabetes mellitus that is either poorly controlled or complicated by
    significant renal or cardiovascular disease

-   Severe hematologic disease

-   Active peptic ulcer

-   Disorders of humoral or cellular immunity

-   Cushing's disease

-   Addison's disease

-   Presence of glaucoma requiring treatment with non-selective
    beta-blockers

-   History of malignancy except for localized basal cell or squamous
    cell carcinoma of the skin that has been resected and patients
    curatively treated and disease free for at least 2 years may be
    considered for entry after discussion with the Glaxo Wellcome
    medical advisor

-   Inadequately controlled psychiatric illness

-   Mental retardation

-   Peripheral vascular disease

-   Use of a pacemaker

7.  Requirement for supplemental oxygen with the following exceptions:

-   Lives at an altitude above 3000 feet and does not require more than
    2 L of oxygen per minute for more than 12 hours per day

-   Does not require more than 2 L of oxygen per minute for more than 2
    hours per day for exertion

8.  A known or suspected hypersensitivity to inhaled corticosteroids,
    beta-agonists or lactose. Gastrointestinal lactose intolerance is
    not an exclusion criterion.

9.  A known or suspected history of alcohol or drug abuse within the
    previous two years

10. 12-lead ECG at screening is abnormal and clinically significant

11. A moderate or severe exacerbation of COPD during the run-in period

12. Chest X-ray reveals clinically significant abnormalities not
    believed to be due to the presence of COPD

13. Received an investigational drug within 30 days prior to entry into
    the run-in period

14. A participating investigator, sub-investigator, study coordinator,
    or employee of a participating investigator, or an immediate family
    member of the aforementioned

15. An abnormal and clinically significant laboratory test a the
    screening visit which is still abnormal on repeat analysis

16. Previous participation in a fluticasone and/or salmeterol study via
    the Diskus for COPD

*[Reviewer comment:]{.underline}*

*The sponsor uses an ATS definition of asthma from 1987. This definition
makes no reference to the role of inflammation in asthma. A more
appropriate definition might be the National Asthma Education and
Prevention Program (NAEPP) definition of asthma, which refers to
inflammation as well as reversible airway obstruction^5^. Taken
strictly, this exclusion criterion would exclude all patients who have
reversible airway obstruction.*

### Protocol amendments

There were three protocol amendments, dated 12/17/98, 2/14/00, and
6/23/00 \[clinstat\\copd\\sfca3007.pdf, page 7208\]. A substudy protocol
for genotyping during the study was also added on 11/4/98
\[clinstat\\copd\\sfca3007.pdf, page 7214\]. This substudy will not be
reviewed.

The FEV~1~/FVC ratio required for entry into the study was changed from
≤65% to ≤70% in Protocol Amendment 1 \[clinstat\\copd\\sfca3007.pdf,
page 7198\]. Originally, the protocol called for approximately 600
patients to be randomized at approximately 55 study centers. The
protocol was amended on 2/15/00 in Protocol Amendment 2 to allow for
approximately 720 patients to be randomized at approximately 75 study
centers and to provide a subgroup analysis of patients who had an
increase in percent of predicted FEV~1~ less than 10% after albuterol at
the screening visit \[clinstat\\copd\\sfca3007.pdf, pages 7206\]. The
protocol was amended to provide subgroup analyses of former smokers, and
of current smokers in Protocol Amendment 3
\[clinstat\\copd\\sfca3007.pdf, pages 7212\].

*[Reviewer comment:]{.underline}*

*The effect of the change in the FEV~1~/FVC ratio would be to allow
entry of patients with both those with milder obstruction (who would be
perhaps more likely to have reversibility) and those with very severe
obstruction with accompanying air trapping. This amendment was made
after the study had been started. The inclusion criteria specifying the
FEV~1~ and the level of dyspnea will minimize any impact of this change.
Other protocol amendments otherwise included minor changes to wording
and study design that had little impact on the evaluation of efficacy or
safety.*

### Study procedures

Study procedures are displayed in Table 1.3.1. Patients provided an
informed consent, and received a medical history and physical
examination at the screening visit. Chest X-ray, pregnancy test,
screening labs, and ECGs were performed. Spirometry with assessment of
reversibility was also performed. Reversibility was assess by performing
spirometry 30 minutes after patient self-administration of 4 puffs of
Ventolin MDI without a spacer or holding chamber
\[clinstat\\copd\\sfca3007.pdf, page 7118\].

There was a two-week, single blind, run-in period for patients meeting
entrance criteria. Patients discontinued all prohibited concurrent
medications and were given Ventolin MDI or nebules to be used as needed
for the duration of the trial, including the run-in. Patients received
placebo via the Diskus BID during the run-in
\[clinstat\\copd\\sfca3007.pdf, pages 7118-7119\]. The purpose of the
single blind run-in period was to establish baseline pulmonary function
and diary card data for at least 10 of the 14 days. Patient compliance
with medication and recording of diary data was also assessed
\[clinstat\\copd\\sfca3007.pdf, page 7118\]. Patient were to record
daily morning PEFRs, nighttime awakenings requiring Ventolin use, use of
rescue Ventolin, and any medical problems experienced
\[clinstat\\copd\\sfca3007.pdf, page 7119\].

Criteria for patients to be eligible for randomization included the
following \[clinstat\\copd\\sfca3007.pdf, page 7119\]:

-   At least 70% compliant with study medication during the run-in

-   Completed diary data for at least 10 of the 14 days of the run-in

-   Had not started or stopped smoking during the run-in

-   Proficiency in use of the peak flow meter

-   Able to safely withhold prohibited study medications

-   Had not experienced a moderate or severe COPD exacerbation

-   Scores ≥4 on the Chronic Bronchitis Symptom Questionnaire (CBSQ)

Patients who completed the run-in period and met all randomization
criteria were assigned to one of four double-blind treatments via the
Diskus for 24 weeks \[clinstat\\copd\\sfca3007.pdf, pages 7111-7112\]:

-   FP 250 mcg BID via Diskus (1 inhalation BID)

-   Salmeterol (SAL) 50 mcg BID via Diskus (1 inhalation BID)

-   Salmeterol (SAL) 50 mcg/FP 250 mcg via Diskus (1 inhalation BID)

-   Placebo via Diskus BID

Assignment to study drug was to be stratified according to the patients'
response to reversibility testing with Ventolin at screening to a
non-reversible group and a reversible group. Non-reversible patients
were defined as having an absolute volume increase \<200 mL or an
absolute volume increase of ≥200 mL with baseline FEV~1~ reversibility
of \<12%. Reversible patients were defined as having an absolute volume
increase ≥200 mL with baseline FEV~1~ reversibility of ≥12%
\[clinstat\\copd\\sfca3007.pdf, page 7113\].

*[Reviewer comment:]{.underline}*

*The definition of reversibility is critical for this study. In
addition, the proportion of patients with reversible obstruction is also
critical, even if the proportion in each of the four treatment groups is
similar. FP and SAL are effective for treatment of asthma, and inclusion
of a high proportion of patients with a significant degree of
reversibility would be likely to result in an overstatement of efficacy
for the entire group. Although assignment to study drug was stratified
according to reversibility based on the above definition, no analysis
was planned or provided for these subgroups. Instead, subgroup analysis
was provided for subgroups based on a different definition. This issue
and its effects are discussed in Section 11.3.16.1 of this document,
\"Data sets analyzed".*

Patients were evaluated weekly for the first four weeks of treatment,
every two weeks until week 8, and then every four weeks for the
remainder of the study. Patients who developed an exacerbation could be
treated with antibiotic therapy as an outpatient for two exacerbations,
but were discontinued from the study if a third exacerbation occurred.
Subjects with exacerbations requiring treatment with systemic
corticosteroids were to be discontinued from the study
\[clinstat\\copd\\scfa3007.pdf, page 7015\].

Patient evaluations at each of the clinic visits included spirometry.
Symptoms were also evaluated with the Baseline/Transition Dyspnea Index
(BDI/TDI), Chronic Bronchitis Symptom Questionnaire (CBSQ), and
assessment of the severity of any COPD exacerbations since the last
evaluations. Health outcomes were assessed with the Chronic Respiratory
Disease Questionnaire (CRDQ), a health-related quality of life
instrument \[clinstat\\copd\\sfca3007.pdf, page 7119\]. The BDI/TDI,
CBSQ, and CRDQ instruments and the instrument for assessment of COPD
exacerbations are described below in Section 11.3.12, Assessment of
signs and symptoms. Cosyntropin stimulation testing was performed at
selected sites.

Patients completed diary cards during the treatment period. Patients
measured PEFRs in triplicate prior to the morning dose of study
medication. The highest of 3 PEFR values was recorded on diary card.
Patients also were to record nighttime awakenings requiring Ventolin
use, the use of supplemental Ventolin, any medical problems, any need
for other concomitant medication, and AEs
\[clinstat\\copd\\sfca3006.pdf, page 7123\].

Table 11.3.1. Study outline, SFCA3007 \[clinstat\\copd\\sfca3007.pdf,
page 7202\].

<table>
<colgroup>
<col style="width: 19%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td><strong>Screen</strong></td>
<td><strong>Run-in</strong></td>
<td colspan="11"><strong>Double-blind treatment period</strong></td>
<td><strong>DC</strong></td>
</tr>
<tr class="even">
<td><strong>Visit number</strong></td>
<td></td>
<td></td>
<td><strong>1</strong></td>
<td><strong>2</strong></td>
<td><strong>3</strong></td>
<td><strong>4</strong></td>
<td><strong>5</strong></td>
<td><strong>6</strong></td>
<td><strong>7</strong></td>
<td><strong>8</strong></td>
<td><strong>9</strong></td>
<td><strong>10</strong></td>
<td><strong>11</strong></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Treatment Day/Week</strong></td>
<td></td>
<td><p><strong>Day</strong></p>
<p><strong>–14 to 1</strong></p></td>
<td><strong>Day 1</strong></td>
<td><strong>Wk 1</strong></td>
<td><strong>Wk 2</strong></td>
<td><strong>Wk 3</strong></td>
<td><strong>Wk 4</strong></td>
<td><strong>Wk 6</strong></td>
<td><strong>Wk8</strong></td>
<td><strong>Wk 12</strong></td>
<td><strong>Wk 16</strong></td>
<td><strong>Wk 20</strong></td>
<td><strong>Wk 24</strong></td>
<td></td>
</tr>
<tr class="even">
<td>Informed consent</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Medical history</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Smoking cessation counseling</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Chest X-ray</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Physical examination</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Pregnancy test</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Reversibility test</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Review inhalation technique</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Medical Research Council Questionnaire</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Clinical laboratory tests</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>12-lead ECG and rhythm strip</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Vital signs</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Cosyntropin stimulation testing*</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Oropharyngeal exam</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Review smoking status</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>AE detection</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Spirometry testing</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Exacerbation assessment</td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Dispense/review diary card</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Chronic bronchitis symptom questionnaire</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>BDI/TDI dyspnea scale</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Quality of life questionnaire</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>Dispense PEFR devices and Ventolin MDI/nebules</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Dispense study medication</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Concurrent medication assessment</td>
<td>X</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Discharge from study</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
</tr>
</tbody>
</table>

\*Selected sites

### Allowable concurrent medications

Allowable concurrent medications included
\[clinstat\\copd\\sfca3007.pdf, page 7114\]:

-   Inhaled Ventolin MDI and/or nebules, provided by the sponsor for use
    as relief medication. Ventolin was to be withheld for at least 6
    hours prior to each treatment visit.

-   Antibiotics were permitted for treatment of two exacerbations.
    Patients were dropped from the study if a third COPD exacerbation
    occurred.

-   Antidepressants other than MAO inhibitors and tricyclic
    antidepressants

-   Theophylline, if on a stable dose for at least one month prior to
    screening

### Prohibited medications

The following medications were prohibited
\[clinstat\\copd\\scfa3007.pdf, page 7115\]:

-   Corticosteroids other than the study medication

-   Beta-agonists other than the Ventolin supplied by the sponsor

-   Concurrent use of any other prescription or over-the-counter
    medication which may affect the course of COPD or interact with
    study medications. These medications were to be discontinued at
    least 2 weeks prior to randomization.

### Drug product and placebo

The sponsor provided the following study treatments
\[clinstat\\copd\\sfca3007.pdf, pages 46-47\]:

-   Placebo Diskus, for the single-blind run-in period and 24-week
    treatment period

-   FP Diskus 250 mcg, 1 puff BID for the 24-week double-blind study
    period

-   SAL Diskus 50 mcg, 1 puff BID for the 24-week double-blind study
    period

-   SAL 50 mcg/FP Diskus 250 mcg, 1 puff BID for the 24-week
    double-blind study period

-   Market-image Ventolin MDI and nebules for each subject as rescue
    medication

-   Cortrosyn 0.25 mg injection for cosyntropin stimulation testing at
    selected sites

The batch numbers of medication were used in this study are displayed in
Table 11.3.2.

Table 11.3.2. Batch numbers of study medication, SFCA3007
\[clinstat\\copd\\scfa3007.pdf, page 47\].

+-----------------------------------+-----------------------------------+
| **Product**                       | **Batch numbers**                 |
+===================================+===================================+
| Placebo Diskus                    | WP25L4                            |
|                                   |                                   |
|                                   | WP31R9                            |
|                                   |                                   |
|                                   | WP2GHW                            |
+-----------------------------------+-----------------------------------+
| FP Diskus 250 mcg                 | U98/028A                          |
|                                   |                                   |
|                                   | B006597                           |
+-----------------------------------+-----------------------------------+
| SAL Diskus 50 mcg                 | WP2D8B                            |
|                                   |                                   |
|                                   | WP2NLT                            |
|                                   |                                   |
|                                   | WP2T35                            |
|                                   |                                   |
|                                   | B003516                           |
+-----------------------------------+-----------------------------------+
| SAL Diskus 50 mcg/FP Diskus 250   | U97/060C                          |
| mcg                               |                                   |
|                                   | WP2PY5                            |
|                                   |                                   |
|                                   | E99B157                           |
|                                   |                                   |
|                                   | E99B158                           |
+-----------------------------------+-----------------------------------+
| Ventolin MDI, 90 mcg/puff         | 7ZP0053                           |
|                                   |                                   |
|                                   | 7ZP0727                           |
|                                   |                                   |
|                                   | 8ZP0909                           |
|                                   |                                   |
|                                   | 9ZP1288                           |
|                                   |                                   |
|                                   | 0ZP0164                           |
+-----------------------------------+-----------------------------------+
| Ventolin nebules, 0.098%, 2.5     | 980905                            |
| mg/3 mL                           |                                   |
|                                   | 990903                            |
+-----------------------------------+-----------------------------------+
| Cortrosyn 0.25 mg injection       | 2240697731                        |
|                                   |                                   |
|                                   | 2300199731                        |
|                                   |                                   |
|                                   | 2310299731                        |
+-----------------------------------+-----------------------------------+

The sponsor states that the formulations of Flovent used in this study
were representative of the commercial product in terms of input
materials, scale of manufacture, manufacturing equipment, and
manufacturing process. The only differences between the batches of
Flovent that were supplied for this study and the commercial product was
the device coloration. All batches of Ventolin nebules and Ventolin MDI
used in this study were the approved commercial product. The placebo
used in this study was identical to the active product used in this
study except for the absence of active drug \[NDA 20-833, SE1-004,
9/17/01, page 3\].

### Assessment of compliance

Patient compliance with the drug dosing schedule was determined from the
dose counter on the Diskus devices. Patients who were less than 70%
compliant with the use of study medication during the 2-week run-in were
not eligible to be randomized into the study
\[clinstat\\copd\\scfa3007.pdf, pages 71, 7121\].

### Assessment of signs and symptoms

Patient COPD symptoms were evaluated with the Chronic Bronchitis Symptom
Questionnaire (CBSQ), Baseline/Transition Dyspnea Index (BDI/TDI), and
assessment of the severity of any COPD exacerbations since the last
evaluations. These instruments are described below.

The CBSQ was composed of selected questions from the Petty Subject
Evaluation Questionnaire^6^and the Revised Global Petty Questionnaire
for Ease of Cough and Sputum Clearance^7^. The CBSQ evaluated cough
frequency and severity, sputum release, and chest discomfort on a 0 to
4, 5-point scale. Individual scores were summed to provide a Global
Assessment Score (GAS). As noted in the inclusion criteria, patients
must have had a GAS of ≥4 at Treatment Day 1 to qualify for the study
\[clinstat\\copd\\sfca3007.pdf, pages 7122, 7133\].

Additional data describing the CBSQ were included with the application.
These data describe the administration of the CBSQ. The patient was
allowed to read each question along with the interviewer and verbally
select the response that best described the status of that particular
symptom on a typical day during the past week. After reading the
question, as written, with the subject, the interviewer used discussion
questions and observations to assist the subject in providing as precise
an answer as possible \[clinstat\\other\\cbsqvalidationdocument.pdf,
page 6\]. A Minimally Clinically Important Change (MCIC) for the CBSQ
was determined to be a change from baseline of 1.4 in the GAS
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 11\]. The
calculation of the MCIC assessed the change in GAS for individual
subjects by collecting them into one of four categories to assess a
Global Rating of Change (GRC)
\[clinstat\\other\\cbsqvalidationdocument.pdf, pages 8-9\]:

1.  GRC = 0, ±1: No change in symptoms of chronic bronchitis

2.  GRC = ±2, ±3: A minimal change in symptoms of chronic bronchitis

3.  GRC = ±4, ±5: A moderate change in symptoms of chronic bronchitis

4.  GRC = ±6, ±7: A large change in symptoms of chronic bronchitis

However the validation package indicates that there was poor correlation
between the GAS and the GRC used to calculate the MCIC. Pearson and
Spearman's correlation coefficients between GAS and GRC were only from
0.25 to 0.34 \[clinstat\\other\\cbsqvalidationdocument.pdf, page 9\].
Furthermore, large standard deviations in the GRC and MCIC were noted.
The standard deviations were large enough for each of the GRC categories
to substantially overlap each other
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 11\].

*[Reviewer comment:]{.underline}*

*The CBSQ was administered in such a fashion that the interviewer might
have influenced patient responses. The poor correlation between the GAS
and GRC and the large standard deviation in the GRC indicate that the
MCIC is not likely to be valid. This instrument will not be able to
provide support for the efficacy of FP.*

The BDI/TDI was used to provide a clinical measurement of baseline and
change in dyspnea. The degree of functional impairment at baseline due
to dyspnea, the magnitude of task to provoke dyspnea, and the magnitude
of effort that provoked dyspnea were rated on a 0 to 4, 5-point scale to
derive the BDI. Changes from baseline in functional impairment,
magnitude of task, and magnitude of effort were assessed at each
subsequent visit with a -3 to +3, seven-point scale, the TDI
\[clinstat\\copd\\sfca3007.pdf, pages 104-105, 7122, 7191-7193\].

The sponsor provided a reference for this instrument which showed a weak
correlation of the BDI with FEV~1~, FVC, and the 12-minute walk distance
with correlation coefficients of 0.41, 0.56, and 0.60^8^. TDI correlated
only weakly with change in the change in the 12-minute walk distance,
with a correlation coefficient of 0.33. There was no correlation of TDI
with change in FEV~1~ or change in FVC. Although not noted in this
study, the sponsor had noted in FLTA3025 that they considered a change
from BDI to TDI of 1.0 to be clinically relevant
\[clinstat\\copd\\flta3025.pdf, page 67, Correspondence submitted to IND
50,703, Meeting request package, 2/6/98\]. The sponsor did not include a
validation package with this application or with the meeting request
package of 2/6/98.

*[Reviewer comment:]{.underline}*

*Degree of functional impairment, magnitude of task, and magnitude of
effort are likely to be highly correlated variables, in this reviewer's
opinion, and therefore will inflate any observed positive or negative
treatment effect. This instrument will not be likely to provide support
for the efficacy of FP because of this deficiency and because of the
lack of validation.*

The investigator assessed the severity of any COPD exacerbations at each
clinic visit using a three-level scale, mild to severe. Mild
exacerbations were defined as use of more than 12 puffs or 4 nebules of
relief bronchodilator per day for more than 2 consecutive days, but
without the need for additional medication. Moderate exacerbations were
defined as requiring either antibiotics or corticosteroids. Severe
exacerbations were defined as requiring inpatient admission for
treatment \[clinstat\\copd\\sfca3007.pdf, page 7122\].

*[Reviewer comment:]{.underline}*

*This is not the standard definition of COPD exacerbation. In fact, this
definition describes situations that reflect a worsening of airway
bronchoconstriction. This definition of exacerbation would be likely to
favor the finding of efficacy of FP in patients who have a high degree
of reversibility. The most widely accepted definition of COPD
exacerbation follows^9^:*

-   *Type 1 = All of the following symptoms*

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```
-   *Increased dyspnea, increased sputum volume, increased sputum
    purulence*

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```
-   *Type 2 = Two of the following symptoms*

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```
-   *Increased dyspnea, increased sputum volume, increased sputum
    purulence*

```{=html}
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```
-   *Type 3 = One of the following symptoms*

```{=html}
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```
-   *Increased dyspnea, increased sputum volume, increased sputum
    purulence and one of the following:*

```{=html}
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```
-   *URI within 5 days, fever without non-respiratory cause, increased
    wheezing, increased coughing, increase in respiratory rate of heart
    rate ≥20%*

Patients were to complete diary records during the treatment period each
morning. Patients recorded the highest of three PEFRs measurements
performed each morning prior the dose of study medication, the number of
inhalations of supplemental Ventolin use over the preceding 24 hours,
and the number of nighttime awakenings requiring the use of Ventolin
during the preceding night \[clinstat\\copd\\sfca3007.pdf, page 7123\].

### Health-related quality of life instrument

Health outcomes were assessed with the Chronic Respiratory Disease
Questionnaire (CRDQ), a health-related quality of life instrument^10^
\[clinstat\\copd\\sfca3007.pdf, page 7124\]. It is worth noting that
comparative quality of life (QOL) was one of the three primary
objectives that the sponsor identified as important outcomes of the
study. The sponsor states that the instrument is an
interviewer-administered, disease-specific, validated questionnaire
designed to measure the impact of chronic respiratory disease and its
treatments on the patient's COPD-related quality of life. The CRDQ is a
20-item questionnaire that evaluates health-related quality of life
across four domains---dyspnea, fatigue, emotional function, and mastery
over the disease. The responses for each of the 20 items were summed to
provide an overall assessment of health-related quality of life. A
physical score was calculated based on the sum of scores of the dyspnea
and fatigue domains and an emotional score was calculated based on the
sum of the scores of the emotional function and mastery domains. The
CRDQ was completed at Day 1, and Weeks 2, 4, 8, 24, and Discontinuation.

### Efficacy variables 

Efficacy variables for this study are described below.

#### Primary efficacy variable

The primary efficacy variables for this study was the pre-dose FEV~1~
and the 2-hour post dose FEV~1~ collected at Day 1, and Weeks 1, 2, 3,
4, 6, 8, 12, 16, 20, and 24 \[clinstat\\copd\\sfca3007.pdf, page 7132\].

For primary efficacy measures, treatments were compared as follows
\[clinstat\\copd\\sfca3007.pdf, page 7132\].

-   SAL 50/FP 250 to SAL 50: Pre-dose FEV~1~, to evaluate the
    contribution of FP 500 to the combination product

-   SAL 50/FP 250 to FP 250: Two-hour post dose FEV~1~, to evaluate the
    contribution of SAL 50 to the combination product

-   SAL 50 to placebo: Two-hour post-dose FEV~1~, to evaluate the
    efficacy of the individual component

-   FP 250 to placebo: Pre-dose FEV~1~, to evaluate the efficacy of the
    individual component

*[Reviewer comment:]{.underline}*

*Only the pre-dose FEV~1~ is relevant to the assessment of efficacy for
FP 250 versus placebo, therefore this comparison will be the focus of
this review. Other active treatment arms will only be discussed only if
relevant to the efficacy and/or safety of FP 250.*

The baseline FEV~1~ was the pre-dose FEV~1~ at treatment Day 1. The
primary analyses compared endpoint and baseline measurements for the
primary efficacy variables. The endpoint was defined in the protocol as
the final evaluable measurement for the patient. For patients who
discontinued from the study the endpoint was the last evaluable
measurement taken prior to withdrawal \[clinstat\\copd\\sfca3007.pdf,
page 7132\]. Therefore, the FEV~1~ at the Discontinuation Visit was not
used for any efficacy analysis.

*[Reviewer comment:]{.underline}*

*As this review is concerned with the efficacy of FP in the treatment of
COPD, only pre-dose FEV~1~ measurements will be examined. Two-hour
post-dose FEV~1~ measurements were performed by the sponsor to help
assess the efficacy of SAL 50 and the contribution of SAL to the
efficacy of the combination SAL 50/FP 250 product.*

*In FLTA3025, the sponsor stated that their rationale for not using the
FEV~1~ at the Discontinuation Visit was that patients might have stopped
taking study drug prior to the visit and might have been taking another
drug that could affect results \[clinstat\\copd\\flta3025.pdf, page
66\]. Although it is not stated in this study, it is likely the sponsor
had the same rationale in this study. The sponsor's plan to carry the
last measurement from the preceding visit forward for discontinuing
patients also affects the interpretation of efficacy results, however.*

Treatment groups were compared using ANCOVA F-tests with baseline as the
covariate. All inferential analyses were performed on the mean change
from Baseline. Ninety-five percent confidence intervals were provided
for treatment differences in the mean changes from Baseline
\[clinstat\\copd\\sfca3007.pdf, pages 71, 7132\].

#### Secondary efficacy variables

Secondary efficacy variables included change from baseline in the global
and individual domains of the CBSQ, the BDI/TDI score at each of the
treatment visits, number and severity of exacerbations of COPD, time to
first COPD exacerbation, number of withdrawals and time to withdrawals.
Morning PEFR, daily use of Ventolin, percentage of nights with no
awakenings requiring Ventolin, frequency of nighttime awakenings
requiring Ventolin, and percent of days without using Ventolin were also
summarized \[clinstat\\copd\\sfca3007.pdf, pages 7122-7123\].

Summary statistics were provided for all secondary endpoints. Changes
from baseline in the Global Assessment Score (GAS) of the CBSQ were
compared between treatment groups using an ANCOVA F-test with treatment
group, investigator, and baseline value as covariates. Overall and
pairwise treatment comparisons of the BDI/TDI scores were performed by
ANOVA F-test. Time to first COPD exacerbation, number of withdrawals,
and time to withdrawals were analyzed using survival analysis
\[clinstat\\copd\\sfca3007.pdf, pages 7132-7133\].

The CRDQ was used to compare changes in the COPD-related quality of life
for treatment groups as measured by an overall score and for each of the
four domains. An improvement of at least 10 in overall score was
considered to be an overall improvement in COPD-specific quality of
life. At each visit, treatment group comparisons were made comparing the
change from baseline using ANCOVA, controlling for baseline and
investigator. A difference between treatment groups in mean change from
baseline was considered clinically meaningful if the difference was
statistically significant and had a minimum of ≥0.5 point improvement
per question per item \[clinstat\\copd\\scfa3007.pdf, pages 7134-7135\].

### Safety variables

Safety variables for this study included AEs, ECGs, hematology and
clinical chemistry studies, oropharyngeal examinations, and vital signs
\[clinstat\\copd\\sfca30007.pdf, pages 60-64, 7124-7128\]. Summary
statistics were to be provided for each of the safety endpoints
\[clinstat\\copd\\sfca3007.pdf, pages 7135-7136\].

*[Reviewer comment:]{.underline}*

*Although the safety variables that were chosen are appropriate to
assess the local and systemic safety of FP, it would have been
preferable to also have formal ophthalmologic examinations and
assessments of bone density, although given the duration of the study,
it is unclear whether such tests would be sufficiently sensitive to
detect a change.*

Cosyntropin (Cortrosyn®) stimulation testing was performed at selected
study sites on Day 1 and Week 24 or Discontinuation
\[clinstat\\copd\\sfca3007.pdf, page 7128\]. The sponsor performed the
short cosyntropin stimulation test according to the cosyntropin package
insert. Blood samples were to be drawn 30-60 minutes after
administration of cosyntropin \[clinstat\\copd\\sfca3007.pdf, page
7128\]. Threshold values of 14.5 mcg/dL and 5.6 mcg/dL were used in the
analysis because a HPLC assay was used. The sponsor states that a less
specific radioimmunoassay was used for the higher reference values given
in the cosyntropin package insert \[clinstat\\copd\\sfca3007.pdf, pages
78-79\].

### Statistical considerations

Imputation of missing data was planned for the primary efficacy
parameter and the humanistic outcomes. Last observation carried forward
analysis was to be performed. \[clinstat\\copd\\sfca3007.pdf, page
7131\].

#### Data sets analyzed

The primary population for the analysis of both efficacy and safety was
the intent-to-treat population, defined as all randomized subjects who
received at least one dose of study drug \[clinstat\\copd\\sfca3007.pdf,
pages 7130-7131\].

Originally, the sponsor did not plan any subgroup analyses
\[clinstat\\copd\\sfca3007.pdf, page 7131\]. In Protocol Amendment 2
(2/17/00), the sponsor added a subgroup analysis for patients who have
an increase in percent predicted FEV~1~ of less than 10% after albuterol
at the screening visit. This group was called the
"poorly-reversible-percent of predicted patients"
\[clinstat\\copd\\sfca3007.pdf, page 7207\]. Subgroup analyses of former
smokers and current smokers were added in Protocol Amendment 3 (6/23/00)
\[clinstat\\copd\\sfca3007.pdf, page 7212\].

*[Reviewer comment:]{.underline}*

*This analysis was to be provided to support the approval of the product
outside the US.* \[clinstat\\copd\\sfca3007.pdf, pages 80, 96\]. *The
sponsor indicates that this definition reflects current opinion of the
European Respiratory Society \[NDA 20-833, SE1-004, pages 1-2,
8/10/01\].*

*As in FLTA3025, SFCA3006, and as noted earlier in this document,
assignment to study drug was to be stratified according to the patients'
response to reversibility testing with bronchodilator at screening to
non-reversible and reversible patients. The non-reversible group was
defined earlier in the protocol as patients with an absolute volume
increase of \<200 mL or absolute volume increase ≥200 mL with baseline
reversibility assessment of \<12% , and is based on the ATS definition
of reversibility \[clinstat\\copd\\sfca3007.pdf, pages 48 7113-7114; NDA
20-833, SE1-004, pages 1-2, 8/10/01\]. As noted earlier, subgroup
analysis initially was not provided for these either the non-reversible
or reversible groups. The proportion of patients with reversibility will
be critical to determine if the population studied accurately reflects
the population of patients with COPD.*

*The sponsor provided an extensive subgroup analysis of the
"poorly-reversible population." As noted above, the poorly-reversible
population" was defined as those patients who had an increase in percent
predicted FEV~1~ of less than 10% after albuterol at the screening
visit. Although this may be the accepted definition for the ERS, it is a
curious way of expressing reversibility, as it uses a theoretical value
as the baseline (percent predicted FEV~1~), rather than an actually
measured value, such as FEV~1~ at baseline. The ERS definition and the
subgroup analysis of the poorly reversible population are not relevant
to approval of this drug for this indication in the US, however, and
this subgroup analysis will receive only brief review.*

#### Statistical power

The sponsor calculated that a sample size of 145 patients per treatment
arm would be necessary to provide \>85% power to detect a clinically
meaningful significant difference of 0.1 liter between treatment groups.
The sponsor assumed a standard deviation for the change from baseline
FEV~1~ of 0.28 liters, and a level of significance of 0.05, using a
two-sample t-test \[clinstat\\copd\\sfca3007.pdf, page 7130\].

The sponsor amended the protocol in Protocol Amendment 2 to allow for
randomization of 720 patients instead of 600 and an increase in the
number of participating centers from 55 to 75
\[clinstat\\copd\\sfca3007.pdf, page 7206\]. The sponsor increased the
planned sample size to account for any data which required exclusion
from the primary efficacy analysis, such as an investigator not meeting
study standards or subjects that have a baseline FEV~1~ assessment
without a subsequent FEV~1~ assessment. The increase in sample size was
also to satisfy the requirement for additional COPD patients to who meet
the European definition of "poorly-reversible" to allow for subgroup
analyses of patient data \[clinstat\\copd\\sfca3007.pdf, page 7206\].

### Results

Efficacy and safety results of this study are reviewed below.

*[Reviewer comment:]{.underline}*

*Review of this study will focus on the efficacy of FP. Therefore
discussion will focus primarily on the comparison of FP 250 and placebo.
Less emphasis will be placed on the comparison of SAL 50 with SAL 50/FP
250, and SAL 50/FP 250 with placebo.*

#### Populations enrolled/analyzed

There were 1489 patients screened for the study. There were 723 patients
who were screening failures. A total of 723 patients were randomized.
The most common reason for screening failure was FEV~1~/FVC \<70% and
baseline FEV~1~ \<65% predicted but \>0.7 L (516/766, 67%). Other
reasons for screening failure included significant concurrent disease
(49/766, 5%), withdrew consent (45/766, 4%), moderate or severe COPD
exacerbation during run-in (36/766, 45%), and inability to tolerate the
2-week run-in (32/766, 4%) \[clinstat\\copd\\sfca3007.pdf, pages 80,
1111-1114\].

*[Reviewer comment:]{.underline}*

*One might expect that failure to tolerate the 2-week run-in would be
the most common reason for screening failure in this study. However,
inability to meet the inclusion criterion for spirometry was the most
common reason for screening failure. This is probably the reason for the
change in Protocol Amendment 1 that changed FEV~1~/FVC ratio from ≤65%
to ≤70%. The most likely effect of this change would be to allow entry
of patients with milder obstruction. These patients might be more likely
to have reversibility, and might be more likely to respond to an inhaled
corticosteroid such as FP.*

Patient disposition is summarized in Table 11.3.3. There were a total of
723 patients randomized and 505 patients completed the study. There were
218 patients that discontinued the study prematurely. The frequency of
discontinuations were fairly similar, with the lowest frequency in FP
250 (50/183, 27%). The most frequent reason for discontinuation for all
groups was COPD exacerbation. Among patients discontinuing the study,
there were 30% (17/32) who discontinued due to COPD exacerbation in the
SAL 50 group, compared with 28% (15/53) in the SAL 50/FP 250 group, 26%
(13/50) in the FP 250 group, and 24% (14/59) in the placebo group. The
frequency of adverse events (AEs) leading to discontinuation was highest
in the FP 250 group (18%, 9/50), followed by the SAL 50/FP 250 group
(17%, 9/53), the placebo group (12%, 7/59), and the SAL 50 group (11%,
6/56). Lack of efficacy was a less frequent reason for discontinuation
in the SAL 50/FP 250 group (6%, 3/53) than for the FP 250 (12%, 6/50),
SAL 50 (14%, 8/56) and placebo (14%, 24/59) groups
\[clinstat\\copd\\sfca3007.pdf, pages 81, 335\].

*[Reviewer comment:]{.underline}*

*It should also be noted that the FP 250 and SAL 50/FP 250 groups
withdrew more frequently because of AEs.*

Table 11.3.3. Patient disposition, SFCA3007,
\[clinstat\\copd\\sfca3007.pdf, pages 81, 335\]

+-----------------+---------+---------+---------+---------+---------+
|                 | **Pl    | **SAL   | **FP    | **SAL   | **      |
|                 | acebo** | 50**    | 250**   | 50/FP   | Total** |
|                 |         |         |         | 250**   |         |
|                 | **N     | **N     | **N     |         | **N     |
|                 | (%)**   | (%)**   | (%)**   | **N     | (%)**   |
|                 |         |         |         | (%)**   |         |
+=================+=========+=========+=========+=========+=========+
| Patients        | 185     | 177     | 183     | 178     | 723     |
| randomized      | (100)   | (100)   | (100)   | (100)   | (100)   |
+-----------------+---------+---------+---------+---------+---------+
| Patients        | 126     | 121     | 133     | 125     | 505     |
| completed       | (68)    | (68)    | (73)    | (70)    | (70)    |
+-----------------+---------+---------+---------+---------+---------+
| Patients        | 59 (32) | 56 (32) | 50 (27) | 53 (30) | 218     |
| discontinued    |         |         |         |         | (30)    |
+-----------------+---------+---------+---------+---------+---------+
| Reason for      |         |         |         |         |         |
| discontinuation |         |         |         |         |         |
+-----------------+---------+---------+---------+---------+---------+
| Adverse event   | 7 (12)  | 6 (11)  | 9 (18)  | 9 (17)  | 31 (14) |
+-----------------+---------+---------+---------+---------+---------+
| COPD            | 14 (24) | 17 (30) | 13 (26) | 15 (28) | 59 (27) |
| exacerbation    |         |         |         |         |         |
+-----------------+---------+---------+---------+---------+---------+
| Withdrawn       | 11 (19) | 9 (16)  | 5 (10)  | 10 (19  | 35 (16) |
| consent         |         |         |         | )       |         |
+-----------------+---------+---------+---------+---------+---------+
| Lack of         | 14 (24) | 8 (14)  | 6 (12)  | 3 (6)   | 31 (14) |
| efficacy        |         |         |         |         |         |
+-----------------+---------+---------+---------+---------+---------+
| Lost to         | 0 (0)   | 3 (5)   | 4 (8)   | 6 (11)  | 13 (6)  |
| follow-up       |         |         |         |         |         |
+-----------------+---------+---------+---------+---------+---------+
| Protocol        | 9 (15)  | 8 (14)  | 9 (18)  | 7 (13)  | 33 (15) |
| violation       |         |         |         |         |         |
+-----------------+---------+---------+---------+---------+---------+
| Other           | 4 (7)   | 5 (9)   | 4 (8)   | 3 (6)   | 16 (7)  |
+-----------------+---------+---------+---------+---------+---------+
| Death           | 0 (0)   | 0 (0)   | 0 (0)   | 0 (0)   | 0 (0)   |
+-----------------+---------+---------+---------+---------+---------+

#### Protocol deviations

The most common violations of inclusion and exclusion criteria included
severity of disease and significant concurrent disease, respectively.
Significant concurrent disease ranged from 2% to 4%. Use of concurrent
medications that interfere with objective assessments ranged from 2% to
5% in the treatment groups \[clinstat\\copd\\sfca3007.pdf, pages 82,
340-341\].

*[Reviewer comment:]{.underline}*

*Violations of inclusion criteria were fairly infrequent and evenly
distributed between treatment groups and were not likely to affect the
analysis of efficacy or safety.*

There were few patients who varied from the protocol who were not
discontinued from the study, as presented in Table 11.3.4. The most
common protocol variations were use of a prohibited corticosteroid, use
of a prohibited non-corticosteroid medication, use of oxygen outside
bounds of protocol, and use of tobacco outside bounds of protocol
\[clinstat\\copd\\scfa3007.pdf, pages 82, 344, 1902-1909\]. Other
protocol variations included inability to use Diskus, inability to
complete diary card, and inability to tolerate the run-in period
\[clinstat\\copd\\scfa3007.pdf, pages 1902-1909\].

Table 11.3.4. Protocol variations during conduct of the study, not
leading to discontinuation, SFCA3007 \[clinstat\\copd\\sfca3007.pdf,
pages 344, 1902-1909\].

+---------------------+-----------+-----------+-----------+-----------+
|                     | **        | **SAL     | **FP      | **SAL     |
|                     | Placebo** | 50**      | 250**     | 50/FP     |
|                     |           |           |           | 250**     |
|                     | **N =     | **N =     | **N =     |           |
|                     | 185**     | 177**     | 183**     | **N =     |
|                     |           |           |           | 178**     |
|                     | **n (%)** |           | **n (%)** |           |
|                     |           |           |           | **n (%)** |
+=====================+===========+===========+===========+===========+
| All protocol        | 19 (10)   | 15 (8)    | 11 (6)    | 16 (9)    |
| variations          |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+
| Used a prohibited   | 5 (3)     | 5 (3)     | 6 (3)     | 6 (3)     |
| corticosteroid      |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+
| Used other          | 7 (4)     | 5 (3)     | 3 (2)     | 6 (3)     |
| prohibited          |           |           |           |           |
| medication          |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+
| Used oxygen         | 1 (\<1)   | 0 (0)     | 0 (0)     | 1 (\<1)   |
+---------------------+-----------+-----------+-----------+-----------+
| Used tobacco        | 0 (0)     | 1 (\<1)   | 0 (0)     | 2 (1)     |
+---------------------+-----------+-----------+-----------+-----------+
| Other               | 7 (4)     | 4 (2)     | 2 (1)     | 4 (2)     |
+---------------------+-----------+-----------+-----------+-----------+

#### Demographic and background characteristics

Demographics and background characteristics of patients are displayed in
Table 11.3.5. The majority of patients in each of the treatment groups
were 65 years of age or older. The mean age of patients was 64.8 years
in the placebo group, 64.2 years in the SAL 50 group, 63.3 years in the
FP 250 group, and 663.4 years in the SAL 50/FP 250 group. Patients
ranged from 40 to 87 years of age. The proportion of patients aged 65
years or less was similar in each of the treatment groups. The age range
was similar in each of the treatment groups.

The majority of patients in this study were of male gender. Males
represented from 58% to 68% of patients in each of the treatment groups.
There were proportionately more males in the placebo group, and
proportionately fewer in the SAL 50 group. The vast majority of patients
in this study were of Caucasian race. There were few patients of Black,
Asian, or Other race. Non-Caucasian races represented 9% or less of each
of the treatment groups.

Patients in this study had fairly severe dyspnea. All patients
experienced dyspnea with walking on level ground, and approximately one
third of the patients in each of the treatment groups had dyspnea with
walking on level ground for 100 yards or worse (MMRC Dyspnea Score ≥3).
The patients in the placebo group had slightly milder dyspnea, with 68%
having a MMRC Dyspnea Score of 2, compared with 61% to 64% with MMRC
Dyspnea Scores of 2 in the other treatment groups. Mean duration of COPD
was approximately 7 to 8 years for each of the treatment groups.
Duration of COPD ranged from 1 year to 53 years.

There was a slightly larger proportion of current smokers in the SAL 50
group (51%, 90/177) than the other treatment groups (43% to 48% for
other groups). The FP 250 group had a slightly larger median history of
smoking (60.0 pack years) than the other treatment groups (523.0 to 57.0
pack years). The median history of smoking was much larger than the 20
pack-year history required for entry into the study.

SAL 50 (20%, 35/177) and SAL 50/FP 250 (41/178, 23%) groups had a
smaller proportion of patients who were using inhaled steroids at
screening than the placebo (55/185, 30%) and FP 250 groups (28%,
51/183). The majority of patients in each treatment group had emphysema.
The frequency of emphysema was similar among treatment groups and ranged
from 63% to 71%.

*[Reviewer comments:]{.underline}*

*The under-representation of non-Caucasian patients in this study is a
deficiency, as in FLTA3025 and SFCA3006. The lack of Black, Asian, and
Hispanic patients will make it impossible to assess efficacy or safety
by race.*

*Overall, the population studied is characterized by long smoking
histories, significant dyspnea, and a 7 to 8 year history of COPD. It is
unclear how the diagnosis of "emphysema" was made for the approximately
65% of the patients who reported it, since the diagnosis would require
HRCT, DLCO, or an invasive procedure. Overall, a fairly large minority
of the patients was taking inhaled corticosteroids at the time of
screening. As noted earlier in this review, one would expect these
patients to more likely to be corticosteroid-responsive than those not
taking inhaled corticosteroids, as one would expect patients with no
response or a poor response to have their treatment discontinued.*

Table 11.3.5. Demographics, SFCA3007 \[clinstat\\copd\\sfca3007.pdf,
pages 84, 345-349\].

+------------------+------------+------------+------------+------------+
| **               | *          | **SAL 50** | **FP 250** | **SAL      |
| Characteristic** | *Placebo** |            |            | 50/FP      |
|                  |            | **N =      | **N =      | 250**      |
|                  | **N =      | 177**      | 183**      |            |
|                  | 185**      |            |            | **N =      |
|                  |            |            |            | 178**      |
+==================+============+============+============+============+
| **Age, years**   | **n (%)**  |            | **n (%)**  | **n (%)**  |
+------------------+------------+------------+------------+------------+
| \<65             | 85 (46)    | 89 (50)    | 95 (52)    | 93 (52)    |
+------------------+------------+------------+------------+------------+
| ≥65              | 100 (54)   | 88 (50)    | 88 (48)    | 85 (48)    |
+------------------+------------+------------+------------+------------+
| Mean age         | 64.8       | 64.2       | 63.3       | 63.4       |
+------------------+------------+------------+------------+------------+
| SD               | 8.7        | 9.8        | 9.4        | 10.6       |
+------------------+------------+------------+------------+------------+
| Range            | 40-81      | 42-87      | 40-84      | 40 -- 87   |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Gender**       | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
+------------------+------------+------------+------------+------------+
| Female           | 59 (32 )   | 75 (42)    | 62 (34)    | 70 (39)    |
+------------------+------------+------------+------------+------------+
| Male             | 126 (68)   | 102 (58)   | 121 (66)   | 108 (61)   |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Race**         | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
+------------------+------------+------------+------------+------------+
| Caucasian        | 173 (94)   | 165 (93)   | 167 (91)   | 170 (96)   |
+------------------+------------+------------+------------+------------+
| Black            | 6 (3)      | 7 (4)      | 9 (5)      | 5 (3)      |
+------------------+------------+------------+------------+------------+
| Asian            | 1 (\<1)    | 0 (0)      | 1 (\<1)    | 0 (0)      |
+------------------+------------+------------+------------+------------+
| Other            | 5 (3)      | 5 (3)      | 6 (3)      | 3 (2)      |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **MMRC Dyspnea   | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
| Score**          |            |            |            |            |
+------------------+------------+------------+------------+------------+
| 2                | 118 (64)   | 120 (68)   | 116 (63)   | 109 (61)   |
+------------------+------------+------------+------------+------------+
| 3                | 58 (31)    | 49 (28)    | 63 (34)    | 63 (35)    |
+------------------+------------+------------+------------+------------+
| 4                | 9 (5)      | 8 (5)      | 2 (1)      | 6 (3)      |
+------------------+------------+------------+------------+------------+
| Missing          | 0 (0)      | 0 (0)      | 2 (1)      | 0 (0)      |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Duration of    | **Years**  | **Years**  | **Years**  | **Years**  |
| COPD**           |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Mean             | 8.02       | 6.96       | 8.22       | 7.53       |
+------------------+------------+------------+------------+------------+
| Range            | 1 -- 36    | 1 -- 30    | 1 -- 53    | 1 -- 43    |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Smoking        | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
| status**         |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Former smoker    | 98 (53)    | 87 (49)    | 95 (52)    | 101 (57)   |
+------------------+------------+------------+------------+------------+
| Current smoker   | 87 (47)    | 90 (51)    | 88 (48)    | 77 (43)    |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Pack-years     |            |            |            |            |
| smoked**         |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Median           | 56.0       | 57.0       | 60.0       | 53.0       |
+------------------+------------+------------+------------+------------+
| Range            | 20 -- 165  | 20 -- 224  | 20 -- 162  | 20 -- 220  |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Inhaled        | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
| steroids at      |            |            |            |            |
| screening**      |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Yes              | 55 (30)    | 35 (20)    | 51 (28)    | 41 (23)    |
+------------------+------------+------------+------------+------------+
| No               | 130 (70)   | 142 (80)   | 132 (72)   | 137 (77)   |
+------------------+------------+------------+------------+------------+
|                  |            |            |            |            |
+------------------+------------+------------+------------+------------+
| **Emphysema**    | **n (%)**  | **n (%)**  | **n (%)**  | **n (%)**  |
+------------------+------------+------------+------------+------------+
| Yes              | 126 (68)   | 116 (66)   | 115 (63)   | 126 (71)   |
+------------------+------------+------------+------------+------------+
| No               | 59 (32)    | 61 (34)    | 68 (37)    | 52 (29)    |
+------------------+------------+------------+------------+------------+

Patients had fairly severe airway obstruction. Spirometry results at the
time of screening are presented in Table 11.3.6. The mean FEV~1~ for
each treatment group of approximately 1275 mL, mean FEV~1~ % predicted
of about 41%, and mean FEV~1~/FVC % of about 42%. The degree of airway
obstruction was slightly less in the FP 250 group (FEV~1~ = 1313 mL,
FEV~1~/FVC% 51.27%) than the other treatment groups
\[clinstat\\copd\\sfca3007.pdf, page 354\].

Table 11.3.6. Spirometry at screening, SFCA3007
\[clinstat\\copd\\sfca3007.pdf, page 354\].

+-------------+-------------+-------------+-------------+-------------+
|             | **Placebo** | **SAL 50**  | **FP 250**  | **SAL 50/FP |
|             |             |             |             | 250**       |
|             | **n = 185** | **n = 177** | **n = 183** |             |
|             |             |             |             | **N = 178** |
+=============+=============+=============+=============+=============+
| **FEV~1~,   |             |             |             |             |
| mL**        |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Mean        | 1289        | 1245        | 1313        | 1252        |
+-------------+-------------+-------------+-------------+-------------+
| SD          | 425         | 432         | 439         | 404         |
+-------------+-------------+-------------+-------------+-------------+
| Median      | 1190        | 1120        | 1240        | 1175        |
+-------------+-------------+-------------+-------------+-------------+
| Range       | 620 -- 2580 | 700 -- 2600 | 640 -- 2690 | 660 -- 2830 |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **FEV~1~, % |             |             |             |             |
| predicted** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Mean        | 42.05       | 41.94       | 41.96       | 41.37       |
+-------------+-------------+-------------+-------------+-------------+
| SD          | 12.24       | 12.04       | 11.33       | 11.28       |
+-------------+-------------+-------------+-------------+-------------+
| Median      | 40.74       | 40.63       | 41.60       | 41.21       |
+-------------+-------------+-------------+-------------+-------------+
| Range       | 17.9 --     | 18.3 --     | 18.9 --     | 17.1 --     |
|             | 67.6        | 70.4        | 66.2        | 64.1        |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| *           |             |             |             |             |
| *FEV~1~/FVC |             |             |             |             |
| %**         |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Mean        | 49.63       | 50.83       | 51.27       | 49.48       |
+-------------+-------------+-------------+-------------+-------------+
| SD          | 11.45       | 9.82        | 10.11       | 10.01       |
+-------------+-------------+-------------+-------------+-------------+
| Median      | 50.44       | 50.99       | 51.34       | 49.07       |
+-------------+-------------+-------------+-------------+-------------+
| Range       | 18.0 --     | 25.4 --     | 27.2 --     | 27.2 --     |
|             | 72.8        | 69.6        | 72.1        | 71.9        |
+-------------+-------------+-------------+-------------+-------------+

Patient response to treatment with bronchodilator at screening is
summarized in Table 11.3.7. A patient was considered "non-reversible"
if, after 4 puffs of Ventolin MDI, there was a change in FEV~1~ of \<12%
from baseline or there was \<200 mL absolute increase in the FEV~1~.
Reversible patients represented 55% of all patients in this study. The
mean % change in FEV~1~ for reversible patients was 29.84%.
Non-reversible patients represented 45 % of all patients in this study.
The mean % change in FEV~1~ for non-reversible patients was 8.57%. The
degree of reversibility in each of the treatment groups was similar. The
mean % change in FEV~1~ for all patients was 20.30%
\[clinstat\\copd\\sfca3007.pdf, pages 85, 354-356\].

*[Reviewer comment:]{.underline}*

*As with Studies FLTA3025 and SFCA3006, the proportion of patients with
reversibility enrolled in this study is much higher than is found in the
population of COPD patients at large. There were 55% of patients in this
study who had reversibility. In addition, the degree of reversibility
for the reversible population was high---29.84%. As noted earlier in
this review, one would expect that only up to 30% of patients to have in
increase of ≥15% in FEV~1~ after inhalation of a beta-agonist.^1-4^ The
mean degree of reversibility in the non-reversible population was also
high---8.57%.*

*The high proportion of patients with reversibility in this study is a
critical consideration in determining whether the results of this
population can be generalized to the COPD population as a whole.
Reversible patients were over-represented relative to their prevalence
in the COPD population as a whole, and the degree of reversibility in
these patients is much higher than would be expected for the general
population of patients with COPD. As with FLTA3025 and SFCA3006, this
may have a major impact on the interpretation of the efficacy results of
this study.*

Table 11.3.7. Mean change in FEV~1~ after bronchodilator treatment at
screening, SFCA3007 \[clinstat\\copd\\sfca3007.pdf, pages 85, 354-356\].

+---------------+----------+----------+----------+----------+----------+
|               | **P      | **SAL    | **FP     | **       | **All    |
|               | lacebo** | 50**     | 250**    | SAL50/FP | t        |
|               |          |          |          | 250**    | reatment |
|               | **N =    | **N =    | **N =    |          | groups** |
|               | 185**    | 177**    | 183**    | **N =    |          |
|               |          |          |          | 178**    | **N =    |
|               |          |          |          |          | 723**    |
+===============+==========+==========+==========+==========+==========+
| **Reversible  |          |          |          |          |          |
| patients**    |          |          |          |          |          |
+---------------+----------+----------+----------+----------+----------+
| n (%)         | 102 (55) | 97 (55)  | 100 (55) | 99 (56)  | 398 (55) |
+---------------+----------+----------+----------+----------+----------+
| Mean % change | 29.72    | 30.87    | 28.93    | 29.88    | 2        |
| in FEV~1~     |          |          |          |          | 9.84\*\* |
+---------------+----------+----------+----------+----------+----------+
| **N           |          |          |          |          |          |
| on-reversible |          |          |          |          |          |
| (ATS)         |          |          |          |          |          |
| patients**    |          |          |          |          |          |
+---------------+----------+----------+----------+----------+----------+
| n (%)         | 83 (45)  | 79 (45)  | 83 (45)  | 79 (44)  | 324 (45) |
+---------------+----------+----------+----------+----------+----------+
| Mean % change | 8.58     | 9.56     | 8.19     | 7.93     | 8.57\*\* |
| in FEV~1~     |          |          |          |          |          |
+---------------+----------+----------+----------+----------+----------+
| **All         |          |          |          |          |          |
| patients**    |          |          |          |          |          |
+---------------+----------+----------+----------+----------+----------+
| n (%)         | 185      | 176      | 183      | 178      | 722      |
|               | (100)    | (100)    | (100)    | (100)    | (100)    |
+---------------+----------+----------+----------+----------+----------+
| Mean % change | 20.24    | 21.31    | 19.53    | 20.14    | 2        |
| in FEV~1~     |          |          |          |          | 0.30\*\* |
+---------------+----------+----------+----------+----------+----------+

\*Calculation of response: ([Post-BD FEV~1~ minus Pre-BD FEV~1~) X
100]{.underline}

Pre-BD FEV~1~

> Not reversible if result is \<12% or \<200 mL increase in FEV~1~

Reversible if result is ≥12% and ≥200 mL increase in FEV~1~

\*\*Mean change derived from data for individual treatment group data

Compliance with study treatment was high in this study. These data are
displayed in Table 11.3.8. Approximately 75% to 80% of patients in each
treatment group took 90% or more of the prescribed doses of medication.
The mean number of doses taken was approximately 94% in each treatment
group \[clinstat\\copd\\sfca3007.pdf, pages 87, 411\].

Table 11.3.8. Compliance with study treatment, SFCA3007
\[clinstat\\copd\\sfca3007.pdf, pages 87, 411\].

+-------------+-------------+-------------+-------------+-------------+
|             | **Placebo** | **SAL 50**  | **FP 250**  | **SAL 50/FP |
|             |             |             |             | 250**       |
|             | **n (%)**   | **n (%)**   | **n (%)**   |             |
|             |             |             |             | **n (%)**   |
+=============+=============+=============+=============+=============+
| All         | 184 (100)   | 175 (100)   | 180 (100)   | 174 (100)   |
| patients    |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| \<80%       | 10 (5)      | 14 (8)      | 16 (9)      | 14 (8)      |
| compliance  |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| 80-\<90%    | 28 (15)     | 16 (9)      | 25 (14)     | 30 (14)     |
| compliance  |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| ≥90%        | 146 (79)    | 145 (82)    | 139 (77)    | 130 (74)    |
| compliance  |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Missing     | 0 (0)       | 1 (\<1)     | 1 (\<1)     | 1 (\<1)     |
+-------------+-------------+-------------+-------------+-------------+

#### Primary efficacy endpoint

The primary efficacy endpoint was the mean change in FEV~1~ from
Baseline to study endpoint. As noted earlier in this review, this review
is concerned with the efficacy of FP in the treatment of COPD. Therefore
only pre-dose FEV~1~ measurements will be examined. The two-hour
post-dose FEV~1~ measurements were performed by the sponsor to help
assess the efficacy of SAL 50 and the contribution of SAL to the
efficacy of the combination SAL 50/FP 250 product, and these will not be
examined in this review. Data for the primary efficacy variable are
displayed in Table 11.3.9. Inferential analysis of the primary efficacy
variable is displayed in Table 11.3.10.

The mean change from baseline in FEV~1~ for the FP 250 group at endpoint
was 109 mL, which was 108 mL more than the placebo group at endpoint.
This comparison was statistically significant at p \<0.001. This change
corresponds to an effect size of 8.7%[^3]. Mean change from baseline in
FEV~1~ for the SAL 50/FP 250 group at endpoint was 165 mL, which was 74
mL more than the SAL 50 group. SAL 50/FP 250 was statistically different
from the SAL 50 group at p = 0.012. Values for the mean change in FEV~1~
from baseline for the FP 250 group at Weeks 6, 12, and 24 were 77 mL, 83
mL, and 118 mL, respectively. Values for the mean change in FEV~1~ for
the placebo group at Weeks 6, 12, and 24 were 47 mL, 11 mL, and 3 mL,
respectively. Values for the mean change from baseline in FEV~1~ for the
SAL 50/FP 250 group at Weeks 6, 12, and 24 were 179 mL, 166 mL, and 165
mL, respectively. Values for the mean change from baseline in FEV~1~ for
the SAL 50 group at weeks 6, 12, and 24 were 129 mL, 107 mL, and to 102
mL, respectively \[clinstat\\copd\\sfca3006.pdf, pages 97, 479-484\].

The mean change from baseline in FEV~1~ for the FP 250 group at Weeks 1,
2, 3, 4, 8, 16, and 20 increased from 83 mL at Week 1 to 113 mL at Week
20 \[clinstat\\copd\\sfca3007.pdf, pages 479-484\].

The mean percent change from baseline in FEV~1~ for FP 250 rose quickly
at the Week 1 visit, with a slow rise to endpoint levels over the
remaining course of treatment \[Sponsor Figure 7.2,
clinstat\\copd\\sfca3007.pdf, page 122\].

*[Reviewer comments:]{.underline}*

*FP 250 met the pre-defined criteria for efficacy for the primary
endpoint, change from baseline to endpoint in pre-dose FEV~1~. FP 250
contributed to the efficacy of the SAL 50/FP 250 combination, as
evidenced in the comparison of SAL 50 with SAL 50/FP 250. All three
active treatments were numerically superior to placebo at Week 1. As
seen with FP 500 in SFCA 3006, the rapid increase from baseline in
FEV~1~ for FP 250 is somewhat of a surprise, as one would have expected
a slower improvement in FEV~1~ for an inhaled corticosteroid. The slower
rise from Week 1 to endpoint levels for FP 250 is more representative of
the expected response to inhaled corticosteroids.*

**Table 11.3.9. Mean change in pre-dose FEV~1~ from baseline, primary
efficacy variable, SFCA3007 \[clinstat\\copd\\sfca3007.pdf, pages 97,
479-484\].**

  ---------------- --------- ----------- ------- --------- ----------- ------- --------- ----------- ------- --------- ----------- -------
                   **Pbo**                       **SAL                         **FP                          **SAL                 
                                                 50**                          250**                         50/FP                 
                                                                                                             250**                 

  **Study week**   **Mean    **Mean      **n**   **Mean    **Mean      **n**   **Mean    **Mean      **n**   **Mean    **Mean      **n**
                   FEV~1~,   change from         FEV~1~,   change from         FEV~1~,   change from         FEV~1~,   change from 
                   mL**      baseline,           mL**      baseline,           mL**      baseline,           mL**      baseline,   
                             mL**                          mL**                          mL**                          mL**        

  **Baseline**     1232      NA          185     1205      NA          177     1236      NA          183     1207      NA          178

  **Week 6**       1318      47          148     1352      129         145     1322      77          157     1386      179         158

  **Week 12**      1284      11          139     1334      107         135     1326      83          147     1375      166         144

  **Week 24**      1287      3           125     1359      102         119     1386      118         133     1412      165         124

  **Endpoint\***   1240      1           172     1303      91          168     1351      109         175     1375      165         171
  ---------------- --------- ----------- ------- --------- ----------- ------- --------- ----------- ------- --------- ----------- -------

\*Primary efficacy endpoint

**Table 11.3.10. Inferential analysis of baseline and change from
baseline in pre-dose FEV~1~**, primary efficacy variable, SFCA3007,
\[clinstat\\copd\\sfca3007.pdf, pages 485-486\].

+---------+--------------+--------------+--------------+--------------+
| **Study | **Overall**  | **Pbo**      | **Pbo**      | **SAL 50**   |
| week**  |              |              |              |              |
|         | **p          | **vs. FP     | **vs. SAL    | **vs. SAL    |
|         | value\***    | 250**        | 50/FP 250**  | 50/FP 250**  |
|         |              |              |              |              |
|         |              | **p          | **p          | **p          |
|         |              | value\***    | value\***    | value\***    |
+---------+--------------+--------------+--------------+--------------+
| Endpo   | \<0.001      | \<0.001      | \<0.001      | 0.012        |
| int\*\* |              |              |              |              |
+---------+--------------+--------------+--------------+--------------+

\*ANCOVA, Baseline as covariate

\*\*Primary efficacy endpoint

#### Secondary efficacy endpoints

Secondary efficacy variables included change from baseline in the global
and individual domains of the CBSQ, the BDI/TDI score at each of the
treatment visits, number and percent of exacerbations of COPD, time to
first COPD exacerbation, number of withdrawals and time to withdrawals.
Morning PEFR, daily use of Ventolin, percentage of nights with no
awakenings requiring Ventolin, frequency of nighttime awakenings
requiring Ventolin, and percent of days without using Ventolin were also
summarized \[clinstat\\copd\\sfca3007.pdf, pages 7122-7123\]. The CRDQ
was also used to compare changes in the COPD-related quality of life for
treatment groups as measured by an overall score and for each of the
four domains.

Summary statistics were provided for all secondary endpoints. Changes
from baseline in the Global Assessment Score (GAS) of the CBSQ were
compared between treatment groups using an ANCOVA F-test with treatment
group, investigator, and baseline value as covariates. Overall and
pairwise treatment comparisons of the BDI/TDI scores were performed by
ANOVA F-test. Time to first COPD exacerbation, number of withdrawals,
and time to withdrawals were analyzed using survival analysis
\[clinstat\\copd\\sfca3007.pdf, pages 7132-7133\]. For the CRDQ,
treatment group comparisons were made comparing the change from baseline
at each visit using ANCOVA, controlling for baseline and investigator
\[clinstat\\copd\\sfca3007.pdf, pages 7134-7135\].

*[Reviewer comment]{.underline}:*

*Inferential analysis is appropriate only for the prospectively defined
efficacy endpoint on which the study was powered, and not for these
secondary efficacy endpoints. Therefore, this document will focus on the
numerical differences between treatment groups for the secondary
efficacy endpoints, and will not address the inferential statistical
analysis.*

##### Chronic Bronchitis Symptom Questionnaire

The CBSQ evaluated cough frequency and severity, sputum release, and
chest discomfort on a 0 to 4, 5-point scale. Individual scores were
summed to provide a Global Assessment Score (GAS). The maximum possible
GAS was 16 \[clinstat\\copd\\sfca3007.pdf, pages 7122, 7123\]. Patients
were required to have a minimum score of 4 at baseline to qualify for
randomization. The sponsor determined that the Minimally Clinically
Important Change (MCIC) in the CBSQ was 1.4 points in an analysis of
patients completing at least 8 weeks of this study
\[clinstat\\other\\cbsqvalidationdocument.pdf, page 11\]. Results of the
Chronic Bronchitis Symptom Questionnaire are displayed in Table 11.3.11.
The sponsor reported clinically important decreases in the CBSQ for FP
250 at Week 2 through Week 24 and at endpoint. The sponsor reported
clinically important decreases in the CBSQ for SAL 50 at endpoint and
Week 6 through Week 24. The sponsor reported clinically important
decreases in the CBSQ for SAL 50/FP 250 at endpoint and Week 2 through
Week 24. The sponsor reported clinically important decreases in the CBSQ
for the placebo group at Weeks 4, 8, 12, 20, 24, and at endpoint.
Decreases in the CBSQ for active treatment

**Table 11.3.11. Chronic Bronchitis Symptom Questionnaire, SFCA3007. See
text for comments. \[clinstat\\copd\\sfca3007.pdf, pages 102,
508-513\]**

  -------------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ -------
                 **Pbo**                          **SAL 50**                       **FP 250**                       **SAL 50/FP              
                                                                                                                    250**                    

  **Study week** **GAS\***   **Mean       **n**   **GAS\***   **Mean       **n**   **GAS\***   **Mean       **n**   **GAS\***   **Mean       **n**
                             change from                      change from                      change from                      change from  
                             baseline**                       baseline**                       baseline**                       baseline**   

  **Baseline**   7.5         NA           185     7.0         NA           177     7.4         NA           183     7.3         NA           178

  **Week 1**     7.0         0.5          170     6.3         0.8          166     6.7         0.7          174     6.2         1.0          170

  **Week 2**     6.6         0.8          167     6.0         1.1          161     5.9         1.4          166     5.4         1.9          165

  **Week 3**     6.5         0.9          158     5.9         1.2          157     5.6         1.8          161     5.1         2.1          159

  **Week 4**     6.0         1.4          155     5.9         1.2          154     5.7         1.7          160     5.1         2.1          161

  **Week 6**     6.1         1.3          149     5.5         1.7          145     5.6         1.8          158     5.1         2.1          159

  **Week 8**     6.0         1.4          147     5.5         1.6          144     5.5         1.8          151     5.2         2.1          152

  **Week 12**    6.0         1.4          139     5.4         1.6          136     5.2         2.2          147     5.0         2.3          144

  **Week 16**    6.0         1.3          132     5.3         1.8          135     5.2         2.2          138     5.1         2.3          136

  **Week 20**    5.9         1.5          127     5.1         2.0          123     5.1         2.3          133     4.9         2.4          129

  **Week 24**    5.6         1.8          126     5.2         1.9          121     4.9         2.5          133     4.8         2.5          125

  **Endpoint**   6.1         1.4          172     5.6         1.5          169     5.2         2.2          175     5.2         2.1          172
  -------------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ -------

\*GAS: Global Assessment Score. Minimally clinically important change =
1.4 points.

groups were numerically superior to placebo at all visits and at
endpoint, except for Week 4 \[clinstat\\copd\\sfca3007.pdf, pages
508-513\].

*[Reviewer comment:]{.underline}*

*Small decreases in the CBSQ were noted for FP 250, SAL 50, and SAL
50/FP 250 at Weeks 1 to 24 and at endpoint. In general, decreases were
numerically superior to placebo. However, the differences from placebo
for all active treatment groups were less than the MCIC of 1.4 points.
These data will not be able to provide support for the efficacy of FP.*

##### Baseline/Transition Dyspnea Indices

The degree of functional impairment at baseline due to dyspnea, the
magnitude of task to provoke dyspnea, and the magnitude of effort that
provoked dyspnea were rated on a 0 to 4, 5-point scale to derive the
BDI. The maximum BDI score was 12. The TDI assessed changes from
baseline in functional impairment, magnitude of task, and magnitude of
effort were assessed at each subsequent visit with a -3 to +3,
seven-point scale \[clinstat\\copd\\sfca3007.pdf, pages 104-105, 7122,
7191-7193\]. The sponsor considered a clinically important TDI score to
be ≥1.0 \[clinstat\\copd\\sfca3007.pdf, page 104, Correspondence
submitted to IND 50,703, Meeting request package, 2/6/98\].

Results of the BDI/TDI are presented in Table 11.3.12. All treatment
groups, including placebo, had improvements from baseline in TDI. The
differences between the treatment group TDIs and placebo were less than
the minimal clinically significant TDI of 1.0 point, except for SAL
50/FP 250 at Weeks 2 and 3 \[clinstat\\copd\\sfca3007.pdf, pages 105,
546-549\].

*[Reviewer comment:]{.underline}*

*The population studied included a high percentage of patients with
reversibility with bronchodilator and does not accurately represent the
population of COPD patients. Degree of functional impairment, magnitude
of task, and magnitude of effort are likely to be highly correlated
variables, in this reviewer's opinion, and therefore will tend to
inflate any observed positive or negative treatment effect. This
instrument has not been validated in a COPD population with a high
degree of reversibility, and it is not a widely used scale or one that
is held in high regard. In general, none of the treatment groups had a
clinically significant difference from placebo. These data do not
provide support for the efficacy of FP.*

**Table 11.3.12. Baseline/Transition Dyspnea Index (BDI/TDI), SFCA3007.
See text for comments. \[clinstat\\copd\\sfca3007.pdf, pages 105,
546-549\]**

  -------------- ----------- --------- ------- --------- ------- --------- ------- --------- -------
                             **Pbo**           **SAL             **FP              **SAL     
                                               50**              250**             50/FP     
                                                                                   250**     

  **Study week** **BDI**               **n**   **BDI**   **n**   **BDI**   **n**   **BDI**   **n**

  **Baseline**   5.7                   183     6.1       176     6.2       179     6.1       174

                 **TDI\***             **n**   **TDI**   **n**   **TDI**   **n**   **TDI**   **n**

  **Week 1**     0.3                   170     1.0       165     0.4       172     1.1       170

  **Week 2**     0.6                   167     1.3       161     1.0       166     1.7       165

  **Week 3**     0.6                   157     1.2       155     1.0       161     1.6       159

  **Week 4**     1.0                   155     1.2       154     1.3       159     1.6       159

  **Week 6**     1.2                   149     1.4       145     1.6       157     1.7       159

  **Week 8**     1.4                   147     1.5       144     1.2       151     1.6       152

  **Week 12**    1.5                   139     1.5       136     1.6       147     1.8       144

  **Week 16**    1.6                   131     1.7       135     1.9       137     1.9       136

  **Week 20**    1.6                   127     2.0       123     1.9       133     2.0       129

  **Week 24**    1.7                   126     1.8       121     2.0       132     2.4       125

  **Endpoint**   1.0                   172     1.6       169     1.7       175     1.7       172
  -------------- ----------- --------- ------- --------- ------- --------- ------- --------- -------

\*Minimally clinically significant TDI = 1.0 point.

##### COPD exacerbations

The incidence of COPD exacerbation and moderate to severe COPD
exacerbation was slightly higher for FP 250 than for the other treatment
groups. Moderate to severe exacerbations of COPD were defined as those
requiring oral antibiotics, inhaled or oral corticosteroids, or
inpatient admission for treatment. These data are displayed in Table
11.3.13.

*[Reviewer comment:]{.underline}*

*It is important to note that the definition of COPD exacerbation was
not the standard definition. The sponsor's definition of COPD
exacerbation describes situations that reflect a worsening of airway
bronchoconstriction, and would be likely to favor the finding of
efficacy of FP in patients who have a high degree of reversibility. Even
so, and despite the improvements in FEV~1~ noted, patients treated with
FP 250 had higher incidences of COPD exacerbations than patients treated
with placebo.*

Table 11.3.13. Incidence of COPD exacerbations, SFCA3007
\[clinstat\\copd\\sfca3007.pdf, pages 107, 571-572\].

+------------------------+----------+----------+----------+----------+
|                        | **P      | **SAL    | **FP     | **SAL    |
|                        | lacebo** | 50**     | 250**    | 50/FP    |
|                        |          |          |          | 250**    |
|                        | **N =    | **N =    | **N =    |          |
|                        | 185**    | 177**    | 183**    | **N =    |
|                        |          |          |          | 178**    |
|                        | **n      | **n      | **n      |          |
|                        | (%)**    | (%)**    | (%)**    | **n      |
|                        |          |          |          | (%)**    |
+------------------------+----------+----------+----------+----------+
| Patients with any COPD | 73 (39)  | 65 (37)  | 79 (43)  | 71 (40)  |
| exacerbation           |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| Patients with moderate | 63 (34)  | 55 (31)  | 69 (38)  | 61 (34)  |
| or severe COPD         |          |          |          |          |
| exacerbations          |          |          |          |          |
+------------------------+----------+----------+----------+----------+

Time to COPD exacerbation or withdrawal is summarized in Table 11.3.14.
The proportion of patients with first COPD exacerbation at each month
during the study was similar for the FP 250 and placebo groups. The
proportion of patients with a moderate to severe COPD exacerbation at
each month during the study was slightly higher for the FP 250 group
than the placebo group. The proportion of patients who withdrew from the
study and withdrawals due to COPD exacerbation was similar across
treatment groups.

*[Reviewer comment:]{.underline}*

*These data provide no support for the efficacy of FP in the population
studied.*

Table 11.3.14. Time to COPD exacerbation or withdrawal, SFCA3007

+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| *     |       |       |       |       |       |       |       |       |
| *Time |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| First |       |       |       |       |       |       |       |       |
| COPD  |       |       |       |       |       |       |       |       |
| Ex    |       |       |       |       |       |       |       |       |
| acerb |       |       |       |       |       |       |       |       |
| ation |       |       |       |       |       |       |       |       |
| \     |       |       |       |       |       |       |       |       |
| [clin |       |       |       |       |       |       |       |       |
| stat\ |       |       |       |       |       |       |       |       |
| \copd |       |       |       |       |       |       |       |       |
| \\sfc |       |       |       |       |       |       |       |       |
| a3007 |       |       |       |       |       |       |       |       |
| .pdf, |       |       |       |       |       |       |       |       |
| pages |       |       |       |       |       |       |       |       |
| 5     |       |       |       |       |       |       |       |       |
| 74-57 |       |       |       |       |       |       |       |       |
| 7\]** |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **    |       | **SAL |       | **FP  |       | **SAL |       |
|       | Pbo** |       | 50**  |       | 250** |       | 50/** |       |
|       |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       | **FP  |       |
|       |       |       |       |       |       |       | 250** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve |
|       | ients | nts** | ients | nts** | ients | nts** | ients | nts** |
|       | at    |       | at    |       | at    |       | at    |       |
|       | r     |       | r     |       | r     |       | r     |       |
|       | isk** |       | isk** |       | isk** |       | isk** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 142   | 30    | 144   | 23    | 135   | 36    | 145   | 26    |
| 1     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 117   | 48    | 121   | 39    | 117   | 51    | 130   | 39    |
| 2     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 104   | 58    | 107   | 48    | 102   | 64    | 119   | 46    |
| 3     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 91    | 67    | 101   | 51    | 94    | 70    | 109   | 53    |
| 4     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 88    | 68    | 88    | 61    | 87    | 75    | 95    | 63    |
| 5     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 0     | 71    | 0     | 65    | 0     | 79    | 0     | 71    |
| 6     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| *     |       |       |       |       |       |       |       |       |
| *Time |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| First |       |       |       |       |       |       |       |       |
| Mod   |       |       |       |       |       |       |       |       |
| erate |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| S     |       |       |       |       |       |       |       |       |
| evere |       |       |       |       |       |       |       |       |
| COPD  |       |       |       |       |       |       |       |       |
| Ex    |       |       |       |       |       |       |       |       |
| acerb |       |       |       |       |       |       |       |       |
| ation |       |       |       |       |       |       |       |       |
| \     |       |       |       |       |       |       |       |       |
| [clin |       |       |       |       |       |       |       |       |
| stat\ |       |       |       |       |       |       |       |       |
| \copd |       |       |       |       |       |       |       |       |
| \\sfc |       |       |       |       |       |       |       |       |
| a3007 |       |       |       |       |       |       |       |       |
| .pdf, |       |       |       |       |       |       |       |       |
| pages |       |       |       |       |       |       |       |       |
| 5     |       |       |       |       |       |       |       |       |
| 79-58 |       |       |       |       |       |       |       |       |
| 2\]** |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **    |       | **SAL |       | **FP  |       | **SAL |       |
|       | Pbo** |       | 50**  |       | 250** |       | 50/** |       |
|       |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       | **FP  |       |
|       |       |       |       |       |       |       | 250** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve |
|       | ients | nts** | ients | nts** | ients | nts** | ients | nts** |
|       | at    |       | at    |       | at    |       | at    |       |
|       | r     |       | r     |       | r     |       | r     |       |
|       | isk** |       | isk** |       | isk** |       | isk** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 148   | 22    | 152   | 12    | 148   | 23    | 153   | 17    |
| 1     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 126   | 36    | 129   | 27    | 131   | 37    | 140   | 26    |
| 2     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 112   | 47    | 115   | 36    | 111   | 53    | 124   | 36    |
| 3     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 99    | 56    | 108   | 40    | 103   | 59    | 114   | 43    |
| 4     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 95    | 58    | 93    | 51    | 95    | 65    | 99    | 53    |
| 5     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 0     | 61    | 0     | 55    | 0     | 69    | 0     | 61    |
| 6     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| *     |       |       |       |       |       |       |       |       |
| *Time |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| Study |       |       |       |       |       |       |       |       |
| Withd |       |       |       |       |       |       |       |       |
| rawal |       |       |       |       |       |       |       |       |
| \[cl  |       |       |       |       |       |       |       |       |
| insta |       |       |       |       |       |       |       |       |
| t\\co |       |       |       |       |       |       |       |       |
| pdsfc |       |       |       |       |       |       |       |       |
| a3007 |       |       |       |       |       |       |       |       |
| .pdf, |       |       |       |       |       |       |       |       |
| pages |       |       |       |       |       |       |       |       |
| 5     |       |       |       |       |       |       |       |       |
| 84-58 |       |       |       |       |       |       |       |       |
| 7\]** |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **    |       | **SAL |       | **FP  |       | **SAL |       |
|       | Pbo** |       | 50**  |       | 250** |       | 50/** |       |
|       |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       | **FP  |       |
|       |       |       |       |       |       |       | 250** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve |
|       | ients | nts** | ients | nts** | ients | nts** | ients | nts** |
|       | at    |       | at    |       | at    |       | at    |       |
|       | r     |       | r     |       | r     |       | r     |       |
|       | isk** |       | isk** |       | isk** |       | isk** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 162   | 23    | 162   | 15    | 169   | 14    | 167   | 11    |
| 1     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 150   | 35    | 152   | 25    | 162   | 21    | 159   | 19    |
| 2     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 145   | 40    | 140   | 37    | 150   | 33    | 149   | 29    |
| 3     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 134   | 51    | 136   | 41    | 145   | 38    | 144   | 34    |
| 4     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 130   | 55    | 128   | 49    | 138   | 45    | 135   | 43    |
| 5     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 0     | 59    | 0     | 56    | 0     | 49    | 0     | 50    |
| 6     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| *     |       |       |       |       |       |       |       |       |
| *Time |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| Study |       |       |       |       |       |       |       |       |
| Withd |       |       |       |       |       |       |       |       |
| rawal |       |       |       |       |       |       |       |       |
| due   |       |       |       |       |       |       |       |       |
| to    |       |       |       |       |       |       |       |       |
| COPD  |       |       |       |       |       |       |       |       |
| Ex    |       |       |       |       |       |       |       |       |
| acerb |       |       |       |       |       |       |       |       |
| ation |       |       |       |       |       |       |       |       |
| \     |       |       |       |       |       |       |       |       |
| [clin |       |       |       |       |       |       |       |       |
| stat\ |       |       |       |       |       |       |       |       |
| \copd |       |       |       |       |       |       |       |       |
| \\sfc |       |       |       |       |       |       |       |       |
| a3007 |       |       |       |       |       |       |       |       |
| .pdf, |       |       |       |       |       |       |       |       |
| pages |       |       |       |       |       |       |       |       |
| 5     |       |       |       |       |       |       |       |       |
| 89-59 |       |       |       |       |       |       |       |       |
| 2\]** |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **    |       | **SAL |       | **FP  |       | **SAL |       |
|       | Pbo** |       | 50**  |       | 250** |       | 50/** |       |
|       |       |       |       |       |       |       |       |       |
|       |       |       |       |       |       |       | **FP  |       |
|       |       |       |       |       |       |       | 250** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
|       | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve | **Pat | **Eve |
|       | ients | nts** | ients | nts** | ients | nts** | ients | nts** |
|       | at    |       | at    |       | at    |       | at    |       |
|       | r     |       | r     |       | r     |       | r     |       |
|       | isk** |       | isk** |       | isk** |       | isk** |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 162   | 5     | 162   | 2     | 169   | 2     | 167   | 3     |
| 1     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 150   | 8     | 152   | 4     | 162   | 6     | 159   | 7     |
| 2     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 145   | 9     | 140   | 9     | 150   | 9     | 149   | 10    |
| 3     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 134   | 13    | 136   | 11    | 145   | 11    | 144   | 11    |
| 4     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 130   | 15    | 128   | 15    | 138   | 14    | 135   | 14    |
| 5     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+
| Month | 0     | 16    | 0     | 20    | 0     | 16    | 0     | 17    |
| 6     |       |       |       |       |       |       |       |       |
+-------+-------+-------+-------+-------+-------+-------+-------+-------+

##### PEFR

PEFR data are presented in Table 11.3.15. Overall, there was a small
mean increase from baseline in AM PEFR was for the FP 250 (11.3 L/min)
and SAL 50 (14.7 L/min) groups at the end of the study. A larger mean
increase was observed in the SAL 50/FP 250 group (30.6 L/min). Similar
increases from baseline in AM PEFR was noted for FP 250, SAL 50, and SAL
50/FP 250 for each month during the treatment period
\[clinstat\\copd\\sfca3007.pdf, pages 109, 599-602\].

*[Reviewer comment:]{.underline}*

*Small increases in AM PEFR for the FP 250 group and the SAL 50/FP 250
group compared with placebo and SAL 50 give support for efficacy of FP
250 in this population and are concordant with the findings of the
primary endpoint of change from baseline in pre-dose FEV~1~.*

Table 11.3.15. Mean change from baseline in AM PEFR
\[clinstat\\copd\\sfca3007.pdf, pages 109, 599-602\].

  ------------------------ ------------- ----------- ----------- -----------
                           **Placebo**   **SAL 50**  **FP 250**  **SAL 50/FP
                                                                 250**

  **Baseline**                                                   

  N                        184           176         182         175

  Mean PEFR, L/min         220.3         210.3       220.0       206.1

  **Overall**                                                    

  N                        183           174         177         173

  Mean PEFR, L/min         220.2         225.3       230.7       236.3

  Mean change from         0.8           14.7        11.3        30.6
  baseline, L/min                                                
  ------------------------ ------------- ----------- ----------- -----------

##### Supplemental Ventolin use

Supplemental Ventolin use is summarized in Table 11.3.16. Overall the
SAL 50 and SAL 50/FP 250 groups had small decreases in the number of
puffs of Ventolin used per day compared with placebo. FP 250 had little
change in the number of puffs of Ventolin used per day and the change
was similar to that seen with placebo. The decrease in Ventolin use for
FP 250 ranged from 0 to 0.5 puffs per day for each study month. Overall,
the FP 250, SAL 50, and SAL 50/FP 250 groups had increases in the number
of days without Ventolin use compared with placebo. The decrease for SAL
50/FP 250 was greater than that for SAL 50 or for FP 250. The decrease
in Ventolin use for FP 250 ranged from 2.5% to 8.7% for each study
month.

*[Reviewer comment:]{.underline}*

*The changes in Ventolin use provide little support for the efficacy of
FP 250 in this population.*

Table 11.3.16. Mean change from baseline in supplemental Ventolin use,
SFCA3007 \[clinstat\\copd\\sfca3007.pdf, pages 111, 604-607, 609-613\].

+------------------------+----------+----------+----------+----------+
|                        | **P      | **SAL    | **FP     | **SAL    |
|                        | lacebo** | 50**     | 250**    | 50/FP    |
|                        |          |          |          | 250**    |
+========================+==========+==========+==========+==========+
| **Number of puffs of   |          |          |          |          |
| Ventolin used per      |          |          |          |          |
| day**                  |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| **Baseline**           |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| N                      | 184      | 176      | 181      | 174      |
+------------------------+----------+----------+----------+----------+
| Mean number of puffs   | 4.8      | 4.6      | 4.6      | 5.1      |
+------------------------+----------+----------+----------+----------+
| **Overall**            |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| N                      | 182      | 174      | 177      | 172      |
+------------------------+----------+----------+----------+----------+
| Mean number of puffs   | 5.0      | 3.9      | 4.4      | 4.1      |
+------------------------+----------+----------+----------+----------+
| Mean change from       | 0.1      | -0.7     | -0.2     | -1.0     |
| baseline, puffs        |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| **Percent of days      |          |          |          |          |
| without Ventolin use** |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| **Baseline**           |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| N                      | 184      | 176      | 181      | 174      |
+------------------------+----------+----------+----------+----------+
| Mean % days without    | 24.8     | 25.2     | 24.7     | 24.4     |
| Ventolin use           |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| **Overall**            |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| N                      | 182      | 174      | 177      | 172      |
+------------------------+----------+----------+----------+----------+
| Mean % days without    | 28.7     | 31.6     | 29.5     | 34.2     |
| Ventolin use           |          |          |          |          |
+------------------------+----------+----------+----------+----------+
| Mean change from       | 4.0      | 5.8      | 5.0      | 10.0     |
| baseline,              |          |          |          |          |
|                        |          |          |          |          |
| \% days                |          |          |          |          |
+------------------------+----------+----------+----------+----------+

Nighttime awakenings requiring Ventolin use are summarized in Table
11.3.17. Overall, the FP 250, SAL 50, and SAL 50/FP 250 groups had very
small decreases from baseline in the number of awakenings per night. Of
the active treatment groups, the FP 250 group had the smallest decrease
number of awakenings per night requiring Ventolin. Overall, the FP 250,
SAL 50, and SAL 50/FP 250 groups had small increases in the percent of
nights with no awakenings requiring Ventolin use. Of the active
treatment groups, the FP 250 group had the smallest increase in percent
of nights with no awakenings.

*[Reviewer comment:]{.underline}*

*The small changes from baseline in nighttime awakenings and percent of
nights with no awakenings requiring Ventolin provide little support of
the efficacy of FP 250 in this population.*

*Nighttime awakenings and percent of nights with no awakenings requiring
Ventolin would also be likely to be highly correlated with the sponsor's
definition of COPD exacerbation. As noted earlier the sponsor's
definition of exacerbation would be expected to favor the demonstration
of efficacy of FP in a study population with a high degree of
reversibility.*

Table 11.3.17. Mean change from baseline in nighttime awakenings
requiring Ventolin use, SFCA30007 \[clinstat\\copd\\sfca3007.pdf, pages
113, 614-617, 619-622\]

  --------------------------------------------------------------------------
                           **Placebo**   **SAL 50**  **FP 250**  **SAL 50/FP
                                                                 250**
  ------------------------ ------------- ----------- ----------- -----------
  **Number of awakenings                                         
  per night requiring                                            
  Ventolin**                                                     

  **Baseline**                                                   

  N                        184           175         181         174

  Mean number of           0.23          0.20        0.24        0.24
  awakenings                                                     

  **Overall**                                                    

  N                        181           174         177         172

  Mean number of           0.25          0.174       0.20        0.12
  awakenings                                                     

  Mean change from         0.02          -0.06       -0.03       -0.12
  baseline, awakenings                                           

  **Percent of nights with                                       
  no awakenings requiring                                        
  Ventolin**                                                     

  **Baseline**                                                   

  N                        184           175         181         174

  Mean % nights with no    83.2          84.7        84.9        82.7
  awakenings                                                     

  **Overall**                                                    

  N                        181           174         177         172

  Mean % nights with no    83.3          89.9        89.9        90.8
  awakenings                                                     

  Mean change from         0.3           5.1         4.8         8.3
  baseline, % nights with                                        
  no awakenings                                                  
  --------------------------------------------------------------------------

##### Health-related quality of life instrument

Quality of life assessment was one of the pre-specified objectives of
this study. COPD-related quality of life was evaluated using the Chronic
Respiratory Disease Questionnaire (CRDQ)^10^. The CRDQ contains 20
questions in 4 domains: dyspnea, fatigue, emotional function, and
mastery. An overall score, the sum of the scores for all 20 questions,
was the primary health-related quality of life endpoint. A physical
score was calculated based on the sum of scores in the dyspnea and
fatigue domains and an emotional score was calculated based on the sum
of scores of the emotional function and mastery domains
\[clinstat\\copd\\sfca3007.pdf, page 7124\]. A clinically significant
improvement was considered to be 0.5 points per item. Therefore, an
improvement in the Overall score of at least 10.0 points was considered
to be a clinically significant improvement in COPD-specific quality of
life. As there were different numbers of items per domain, the
clinically significant changes for each domain and summary scores are as
follows \[clinstat\\copd\\sfca3007.pdf, pages 74-77, 7134-7135\]:

-   Fatigue domain: 2.0 points

-   Dyspnea domain: 2.5 points

```{=html}
<!-- -->
```
-   Physical summary: 4.5 points

```{=html}
<!-- -->
```
-   Emotional function domain: 3.5 points

-   Mastery domain: 2.0 points

-   Emotional summary: 5.5 points

Study endpoint was defined as the last available post-baseline score for
the CDRQ. This was different from the other analyses, which did not
include values for the Discontinuation visit
\[clinstat\\copd\\sfca3007.pdf, page 142\]. In addition, the sponsor
excluded patients with an overall baseline score greater than 130 from
the analysis of the overall score at any visit. These patients were
excluded because baseline scores would be mathematically unable to
attain a clinically meaningful change \[clinstat\\copd\\sfca3006.pdf,
page 142\]. Similar exclusions were made for the patients with the
following scores \[clinstat\\copd\\sfca3007.pdf, page 76\]:

-   Fatigue score \>26

```{=html}
<!-- -->
```
-   Dyspnea score \>32

-   Physical summary \>58

-   Emotional function score \>45

-   Mastery score \>26

-   Emotional summary \>71

The population analyzed, which excluded these patients, was referred to
the "reduced intent-to-treat population" (reduced ITT population)
\[clinstat\\copd\\sfca3006.pdf, page 76\].

*[Reviewer comment:]{.underline}*

*It is true that it is be mathematically impossible for patients whose
baseline scores are higher than those noted above to attain a clinically
meaningful change. However, it is not appropriate to exclude these
patients from the analysis. It would have been preferable to set these
maximum scores as inclusion criteria for the study. As it turns out,
there were no patients excluded for the Overall score and the Physical
summary score and the ITT and "reduced ITT populations" were identical
for these scores \[clinstat\\copd\\sfca3007.pdf, pages 143, 769, 775,
1519, 1525\].*

*There were a total of 26 patients among all treatment groups excluded
from the calculation of the Emotional summary score. There were 23
patients excluded from the Emotional function domain score, 63 patients
from the Mastery domain score, 3 patients from the Dyspnea domain, and 1
patient from the Fatigue domain score \[clinstat\\copd\\sfca3007.pdf,
pages 781, 787, 793, 799, 805, 1531, 1537, 1543, 1549, 1555\]. This
review will examine CDRQ results for the ITT group and not the reduced
ITT population.*

There were clinically significant improvements from baseline in the
overall CDRQ score for FP 250 (10.4 points) and SAL 50/FP 250 (10.0
points). However, there was less than a 10.0 point difference in these
values from the change from baseline for the placebo group, and
therefore not a clinically significant difference from the placebo
group. The change in the overall CDRQ score for SAL 50 (6.4 points) was
similar to placebo (5.0 points). These data are displayed in Table
11.3.18. The data displayed reflects the ITT population.

FP 250 and SAL 50/FP 500 had clinically significant improvements from
baseline in the Physical summary score. The change in the Physical
summary score for FP 250 (5.6 points) and SAL 50/FP 250 (6.1 points)
were slightly greater than placebo (3.8 points). However, there was less
than a 4.5 point difference in these values from the change from
baseline for the placebo group, and therefore there was not a clinically
significant difference from the placebo group. No treatment group had a
clinically significant change in the Emotional summary score
\[clinstat\\copd\\sfca3007.pdf, pages 1519, 1525, 1531\].

In general, FP 250 and SAL 50/FP 250 had scores for change from baseline
in individual domains that were numerically superior to scores for
change from baseline for placebo. However, no individual domain score
for FP 250 or SAL 50/PF 250 differed from placebo by the specified
clinically significant amount \[clinstat\\copd\\sfca3007.pdf, pages
1519, 1525, 1531, 1537, 1543, 1549, 1555\].

Examination of the "reduced ITT population" revealed similar findings as
the ITT population \[clinstat\\copd\\sfca3007.pdf, pages 769, 775, 781,
787, 793, 799, 805\].

**Table 11.3.18. Chronic Respiratory Disease Questionnaire (CRDQ),
COPD-related quality of life instrument, ITT population, SFCA3007
\[clinstat\\copd\\sfca3007.pdf, pages 1519, 1525, 1531\].**

  --------------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ -------
                  **Pbo**                          **SAL 50**                       **FP 250**                       **SAL 50/FP              
                                                                                                                     250**                    

                  **Score**   **Mean       **n**   **Score**   **Mean       **n**   **Score**   **Mean       **n**   **Score**   **Mean       **n**
                              change from                      change from                      change from                      change from  
                              baseline**                       baseline**                       baseline**                       baseline**   

  **Overall                                                                                                                                   
  score\***                                                                                                                                   

  **Baseline**    84.8        NA           180     86.3        NA           173     85.5        NA           177     84.1        NA           175

  **Endpoint**    89.6        5.0          177     93.0        6.4          170     96.4        10.4         170     93.9        10.0         169

  **Physical                                                                                                                                  
  summary                                                                                                                                     
  score\*\***                                                                                                                                 

  **Baseline**    32.3        NA           180     33.1        NA           173     33.3        NA           177     32.0        NA           175

  **Endpoint**    35.9        3.8          177     37.0        3.9          170     39.0        5.6          170     38.1        6.1          169

  **Emotional                                                                                                                                 
  summary                                                                                                                                     
  score\*\*\***                                                                                                                               

  **Baseline**    52.6        NA           180     53.2        NA           173     52.2        NA           178     52.1        NA           175

  **Endpoint**    53.6        1.2          177     56.0        2.6          170     57.3        4.7          171     55.8        3.9          169
  --------------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ ------- ----------- ------------ -------

\*Clinically significant change in Overall Score = 10.0 points

\*\*Clinically significant change in Physical Summary Score = 4.5 points

\*\*\*Clinically significant change in Emotional Summary Score = 5.5
points

*[Reviewer comment:]{.underline}*

*Although there were clinically significant improvements from baseline
in the Overall score and the Physical summary scores for FP 250 and SAL
50/FP 250, these improvements were less than the specified clinically
significant difference from the change from baseline in the placebo
group. Since the Overall score did not show any clinically significant
differences from placebo, individual domains or summary scores provide
no meaningful information. These data provide no additional support for
the efficacy of FP in this population.*

#### Smoking status, subgroup analysis

The sponsor provided an analysis of efficacy by patient smoking status.
Former smokers had the largest mean change from baseline in pre-dose
FEV~1~at endpoint in all active treatment groups
\[clinstat\\copd\\sfca3007.pdf, page 115\]. These data are displayed in
Table 11.3.19. Among the former smokers, those treated with SAL 50/FP
250 had the largest change in FEV~1~ (193 mL), followed by those treated
with FP 250 (136 mL), and SAL 50 (86 mL). The smallest change for former
smokers was noted in those treated with placebo (-3 mL). Patients who
were smokers during the conduct of the study had smaller mean changes
from baseline in pre-dose FEV~1~, with the largest change in patients
treated with SAL 50/FP 250 (127 mL), and followed by SAL 50 (96 mL) and
FP 250 (80 mL). The smallest change was in placebo patients (4 mL).

Table 11.3.19. Mean change from baseline in pre-dose FEV~1~ at endpoint,
by smoking status, SFCA3007 \[clinstat\\copd\\sfca3007.pdf, page 115\].

+----------+--------------+--------------+--------------+--------------+
| *        | **Placebo**  | **SAL 50**   | **FP 250**   | **SAL 50/FP  |
| *Smoking |              |              |              | 250**        |
| status** | **Mean**     | **Mean**     | **Mean**     |              |
|          |              |              |              | **Mean**     |
|          | **Change, mL | **change, mL | **change, mL |              |
|          | (n)**        | (n)**        | (n)**        | **change, mL |
|          |              |              |              | (n)**        |
+==========+==============+==============+==============+==============+
| Current  | 4 (87)       | 96 (90)      | 80 (88)      | 127 (77)     |
| smokers  |              |              |              |              |
+----------+--------------+--------------+--------------+--------------+
| Former   | -3 (98)      | 86 (87)      | 136 (95)     | 193 (101)    |
| smokers  |              |              |              |              |
+----------+--------------+--------------+--------------+--------------+

The sponsor also examined other efficacy endpoints by patient smoking
status. In general, where there were differences between the groups,
efficacy was favored in the former smokers for FP 250, as well as in
other active treatment groups. Current smokers had a lower percentage of
COPD exacerbations than former smokers in all treatment groups. Changes
in PEFRs for patients treated with FP 250 were slightly higher in former
smokers than in current smokers, similar to the FEV1 data.

Results of the Overall CRDQ score at endpoint for former smokers or
current smokers in all treatment groups were similar to that seen for
all patients in the intent-to-treat group. Larger changes from baseline
were seen in the FP 250 and SAL 50/FP 500 groups than in SAL 50 and
placebo groups. The degree of change from baseline for FP 350 and SAL
50/FP 250 was fairly similar in former smokers and in current smokers.
However, there was less than a 10.0 point difference in these values
from the change from baseline for the placebo group, indicating that
there was not a clinically significant difference from the placebo group
\[clinstat\\copd\\sfca3007.pdf, page 1583, 1586\].

*[Reviewer comment:]{.underline}*

*These data suggest that in general, efficacy favored patients who
stopped smoking prior to the conduct of the study, as noted in FLTA3025
and SFCA3006. The observation that there were more COPD exacerbations in
former smokers than in current smokers is interesting, but may be due to
a higher number of withdrawals in the current smoker group.*

#### "Non-reversible" population, subgroup analysis

Assignment to study drug was to be stratified according to the patients'
response to reversibility testing with Ventolin at screening to a
non-reversible group and a reversible group. Non-reversible patients
were defined as having an absolute volume increase \<200 mL or an
absolute volume increase of ≥200 mL with baseline FEV~1~ reversibility
of \<12%. Reversible patients were defined as having an absolute volume
increase ≥200 mL with baseline FEV~1~ reversibility of ≥12%
\[clinstat\\copd\\sfca3007.pdf, page 7113; IND 44,090 N134 PN, 8/4/98,
page 25\]. Despite having assignment stratified based on
"non-reversibility," the sponsor did not initially include an analysis
for this subgroup. The sponsor was asked to provide a subgroup analysis
of the non-reversible group in an IR on 10/2/01. The sponsor submitted
this information in a document dated 1/17/01 \[NDA 20-833, SE1 004 BZ,
10/17/01\]. The results of the subgroup analysis for the non-reversible
population are briefly reviewed below.

Table 11.3.20 summarizes the mean change in FEV~1~ from baseline for the
"non-reversible" population. Increases from baseline in pre-dose FEV~1~
at endpoint were noted in all active treatment groups. The largest
increase was in the SAL 50/FP 500 group (126 mL), followed by FP 250 (74
mL), and SAL 50 (26 mL). The placebo group had a an increase from
baseline at endpoint of 19mL \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, pages 13, 377-382\].

A similar pattern was noted for mean change from baseline in pre-dose
FEV~1~ at Weeks 12 and 24. The largest increases were for the SAL 50/FP
500 group, followed by FP 250 and SAL 50. Increases from baseline were
noted at these visits for the placebo group and ranged from 23 mL to 41
mL \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, pages 14,
377-382\].

**Table 11.3.20. Mean change in pre-dose FEV~1~** from baseline, primary
efficacy variable, non-reversible population, SFCA3007 \[NDA 20-833 SE1
004, BZ, 10/17/01\\response.pdf, pages 14, 377-382\].

  -------------- --------- --------- ------- --------- --------- ------- --------- --------- ------- --------- --------- -------
                 **Pbo**                     **SAL                       **FP                        **SAL               
                                             50**                        250**                       50/FP               
                                                                                                     250**               

  **Study week** **Mean    **Mean    **n**   **Mean    **Mean    **n**   **Mean    **Mean    **n**   **Mean    **Mean    **n**
                 FEV~1~,   change,           FEV~1~,   change,           FEV~1~,   change,           FEV~1~,   change,   
                 mL**      mL**              mL**      mL**              mL**      mL**              mL**      mL**      

  **Baseline**   1116      NA        83      1151      NA        79      1098      NA        83      1111      NA        79

  **Week 12**    1224      41        65      1235      83        59      1181      75        65      1270      147       64

  **Week 24**    1213      23        55      1222      27        52      1210      83        59      1295      144       54

  **Endpoint**   1141      19        79      1176      26        74      1170      74        79      1245      126       75
  -------------- --------- --------- ------- --------- --------- ------- --------- --------- ------- --------- --------- -------

Response of the reversible population in the mean change in FEV~1~ from
baseline is summarized in Table 11.3.21. The difference from placebo for
mean change from baseline at endpoint for the reversible group for FP
250 was 153 mL. This was 98 mL greater than the difference from placebo
for mean change from baseline at endpoint for the non-reversible group,
which for FP 500 was 55 mL \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, page 14\].

**Table 11.3.21. Mean change in pre-dose FEV~1~** from baseline, primary
efficacy variable, reversible population, SFCA3007 \[NDA 20-833 SE1 004,
BZ, 10/17/01\\response.pdf, pages 14, 383-388\].

  -------------- --------- --------- ------- --------- --------- ------- --------- --------- ------- --------- --------- -------
                 **Pbo**                     **SAL                       **FP                        **SAL               
                                             50**                        250**                       50/FP               
                                                                                                     250**               

  **Study week** **Mean    **Mean    **n**   **Mean    **Mean    **n**   **Mean    **Mean    **n**   **Mean    **Mean    **n**
                 FEV~1~,   change,           FEV~1~,   change,           FEV~1~,   change,           FEV~1~,   change,   
                 mL**      mL**              mL**      mL**              mL**      mL**              mL**      mL**      

  **Baseline**   1327      NA        102     1237      NA        97      1350      NA        100     1284      NA        99

  **Week 12**    1337      -16       74      1396      127       75      1440      88        82      1459      181       80

  **Week 24**    1346      -13       70      1445      157       66      1547      146       74      1502      180       70

  **Endpoint**   1325      -15       93      1389      141       93      1500      138       96      1476      196       96
  -------------- --------- --------- ------- --------- --------- ------- --------- --------- ------- --------- --------- -------

*[Reviewer comment:]{.underline}*

*Primary efficacy endpoint data provide some support for the efficacy of
FP 250 and SAL 50/FP 250 in the non-reversible population.*

In general, secondary endpoints demonstrated small improvements from
baseline in the non-reversible population for SAL 50/FP 250, but not FP
250.

Changes at endpoint from baseline in the GAS of the CBSQ were noted for
all treatment groups, but there were no clinically significant
differences from the placebo group. Changes at endpoint from baseline in
the GAS were greatest in the SAL 50/FP 250 group and the FP 250 group
\[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, pages 15, 419\].
Changes at endpoint from baseline in the TDI showed no clinically
significant differences from placebo. Changes from baseline in the TDI
were greatest for SAL 50/FP 250 and FP 250 \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, page 479\]. The incidences and frequencies of
COPD exacerbations were similar across the active and placebo treatment
groups for this population. The incidence and frequency of moderate to
severe exacerbations due to COPD were slightly higher in the SAL 50 and
FP 250 groups than the SAL 50/FP 250 and placebo groups. \[NDA 20-833
SE1 004, BZ, 10/17/01\\response.pdf, pages 16, 487, 489\].

*[Reviewer comment:]{.underline}*

*Secondary efficacy endpoint data do not provide support for the
efficacy of FP 250 in the non-reversible population.*

There was a slightly lower probability of first COPD exacerbation during
the first half of the study for the SAL 50/FP 250 group compared with
the other treatment groups. There was a slightly higher probability of
first COPD exacerbation during the first half of the study for the FP
250 group compared with the other treatment groups. However, the
probabilities for first COPD exacerbation were similar for all treatment
groups by the end of the study \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, page 357\]. There was a slightly lower
probability of first moderate to severe COPD exacerbation during the
first half of the study for the SAL 50/FP 250 group compared with the
other treatment groups. There was a slightly higher probability of first
moderate to severe COPD exacerbation during the first half of the study
for the FP 250 group compared with the other treatment groups. However,
the probabilities for first COPD exacerbation were similar for all
treatment groups by the end of the study \[NDA 20-833 SE1 004, BZ,
10/17/01\\response.pdf, page 359\].

In general, small changes from baseline favoring SAL 50/ FP 250, FP 250,
SAL 50 were noted in for the non-reversible population for AM PEFR. The
effect was greatest for the SAL 50/FP 250 group, followed by the SAL 50
and FP 250 groups \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, page
510\].

There was a decrease in the number of puffs of Ventolin used per day for
the SAL 50/FP 250 group. There was no meaningful decrease in the number
of puffs of Ventolin used per day for the FP 250, SAL 50, or placebo
groups \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, page 16\].
Awakenings per night requiring Ventolin showed little meaningful
difference between treatment groups for the non-reversible group \[NDA
20-833 SE1 004, BZ, 10/17/01\\response.pdf, page 526\].

The overall score of the CRDQ, the health-related quality of life
instrument, showed a clinically significant change from baseline for the
SAL 50/FP 500 group. However this change was not clinically
significantly different from the change from baseline for the placebo
group \[NDA 20-833 SE1 004, BZ, 10/17/01\\response.pdf, page 531\].

*[Reviewer comment:]{.underline}*

*AM PEFR was the only secondary endpoint that provided support for FP
250, and this is endpoint is likely to be fairly well correlated with
the primary efficacy endpoint, which also supported FP 250. This
analysis of primary efficacy variable and selected secondary variables
in the non-reversible population provide little support for efficacy of
FP 250.*

#### Safety outcomes

Safety variables for this study included AEs, ECGs, hematology and
clinical chemistry studies, oropharyngeal examinations, and vital signs
\[clinstat\\copd\\sfca30007.pdf, pages 60-64, 7124-7128\].

Cosyntropin (Cortrosyn®) stimulation testing was performed at selected
study sites on Day 1 and Week 24 or Discontinuation
\[clinstat\\copd\\sfca3007.pdf, page 7128\].

##### Total drug exposure

Total drug exposure is summarized in Table 11.3.22. Approximately 62% of
each group completed ≥24 weeks of study treatment. The mean duration of
treatment was 131.6 days for placebo, 136.1 days for SAL 50, 138.5 days
for FP 250, and 141.3 days for SAL 50/FP 250.

Table 11.3.22. Total drug exposure, SFCA3007
\[clinstat\\copd\\sfca3007.pdf, pages 153, 895\].

+-------------+-------------+-------------+-------------+-------------+
| **Duration  | **Placebo** | **SAL 50**  | **FP 250**  | **SAL 50/FP |
| of          |             |             |             | 250**       |
| treatment** | **N = 185** | **N = 177** | **N = 183** |             |
|             |             |             |             | **N = 178** |
|             | **n (%)**   | **n (%)**   | **n (%)**   |             |
|             |             |             |             | **n (%)**   |
+-------------+-------------+-------------+-------------+-------------+
| Any         | 185 (100)   | 177 (100)   | 183 (100)   | 178 (100)   |
| treatment   |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| ≥4 weeks    | 160 (86)    | 157 (89)    | 164 (90)    | 163 (92)    |
+-------------+-------------+-------------+-------------+-------------+
| ≥8 weeks    | 150 (81)    | 151 (85)    | 156 (85)    | 158 (89)    |
+-------------+-------------+-------------+-------------+-------------+
| ≥12 weeks   | 141 (76)    | 138 (78)    | 148 (81)    | 148 (83)    |
+-------------+-------------+-------------+-------------+-------------+
| ≥16 weeks   | 133 (72)    | 134 (76)    | 145 (79)    | 141 (79)    |
+-------------+-------------+-------------+-------------+-------------+
| ≥20 weeks   | 130 (70)    | 127 (72)    | 136 (74)    | 131 (74)    |
+-------------+-------------+-------------+-------------+-------------+
| ≥24 weeks   | 110 (59)    | 108 (61)    | 116 (63)    | 112 (63)    |
+-------------+-------------+-------------+-------------+-------------+
| Treatment   | 131.6       | 136.1       | 138.5       | 141.3       |
| days, mean  |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+

*[Reviewer comment:]{.underline}*

*Drug exposure appears to be adequate to allow for assessment of
short-term safety, and noting the limitations that the design and
duration of this study impose, and recognizing the compliance reporting
is commonly unreliable. Compliance assessment was based on data from the
Diskus dose counter, which cannot assess whether patients actually
received the drug that was dispensed.*

##### Cosyntropin stimulation testing

Cosyntropin (Cortrosyn®) stimulation testing was performed at selected
study sites on Day 1 and Week 24 or Discontinuation
\[clinstat\\copd\\sfca3007.pdf, page 7128\]. The sponsor performed the
short cosyntropin stimulation test according to the cosyntropin package
insert. Blood samples were to be drawn 30-60 minutes after
administration of cosyntropin \[clinstat\\copd\\sfca3007.pdf, page
7128\]. Threshold values of 14.5 mcg/dL and 5.6 mcg/dL were used in the
analysis because a HPLC assay was used. The sponsor states that a less
specific radioimmunoassay was used for the higher reference values given
in the cosyntropin package insert \[clinstat\\copd\\sfca3007.pdf, pages
78-79\].

The sponsor states that this adjustment is consistent with previously
published data^11,\ 12^. Abnormalities for this test was defined as:

-   AM plasma cortisol \<4 mcg/dL

-   Peak post-stimulation cortisol \<14.5 mcg/dL

-   Change from baseline of \<5.6 mcg/dL

-   Peak post-stimulation cortisol \<14.5 mcg/dL and change from
    baseline of \<5.6 mcg/dL

There is no mention in the protocol of the type of assay that was to be
used for cortisol, or of the definitions for abnormalities in cortisol
levels.

*[Reviewer comment:]{.underline}*

*The definitions for abnormalities in cortisol levels with the
cosyntropin stimulation test are consistent with the sponsor's
references. It would have been preferable to specify in the protocol
both the assay to be used and the definitions of an abnormal test,
however.*

The number and percentage of patients with abnormalities in cosyntropin
stimulation testing is displayed in Table 11.3.23. The numbers of
patients with cortisols were incorrect in the initial submission, but
were corrected in a subsequent response NDA 20-833 SE1 004, BZ,
10/26/01\\response.pdf\]. The correct numbers are displayed in Table
1.3.23 and are reviewed in this section. There were no differences
between treatment groups in the percentage of patients who had
pre-stimulation AM cortisol levels \<4 mcg/dL at Day 1 and Endpoint.
There were no differences between treatment groups in the percentage of
patients with a change in post-stimulation cortisol \<5.6 mcg/dL

FP 250 had the largest percentage of patients with post-stimulation
change in cortisol at endpoint of \<5.6 mcg/dL (15%). However, the
percentage of patient with post-stimulation change in cortisol at
endpoint of \<5.6 mcg/dL in the SAL 50/FP 250 group (9%) was similar to
that in the placebo group (11%).

There was an increase in the percentage of patients with
post-stimulation cortisol levels \<14.5 mcg/dL from Day 1 to Endpoint in
all treatment groups. The largest increase in the percentage of patients
with post-stimulation cortisol levels \<14.5 mcg/dL from Day 1 to
Endpoint was in the FP 250 group (6% to 12%). However, the percentage of
patients with post-stimulation cortisol levels \<14.5 mcg/dL in the SAL
50/FP 250 group had a small decrease (4% to 3%). The results of patients
with post-stimulation cortisol levels \<14.5 mcg/dL in the SAL 50 group
(4% to 7%) and placebo group (4% to 7%) were similar
\[clinstat\\copd\\sfca3007.pdf, pages 166, 969, 972\].

Table 11.3.23. Number and percentage of patients with abnormalities in
cosyntropin stimulation testing, all patients with cortisol levels,
SFCA3007 \[clinstat\\copd\\sfca3007.pdf, pages 166, 969, 972; NDA 20-833
SE1 004, BZ, 10/26/01\\response.pdf, page 30\].

+-------------+------+------+------+------+------+------+------+------+
|             | Day  |      |      |      | Endp |      |      |      |
|             | 1    |      |      |      | oint |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
|             | Pbo  | SAL  | FP   | SAL  | Pbo  | SAL  | FP   | SAL  |
|             |      | 50   | 250  | 50/  |      | 50   | 250  | 50/  |
|             | N    |      |      | FP   | N    |      |      | FP   |
|             | =185 | N    | N    | 250  | =185 | N    | N    | 250  |
|             |      | =177 | =183 |      |      | =177 | =183 |      |
|             | n    |      |      | N    | n    |      |      | N    |
|             | (%)  | n    | n    | =178 | (%)  | n    | n    | =178 |
|             |      | (%)  | (%)  |      |      | (%)  | (%)  |      |
|             |      |      |      | n    |      |      |      | n    |
|             |      |      |      | (%)  |      |      |      | (%)  |
+-------------+------+------+------+------+------+------+------+------+
| Patients    | 54   | 53   | 50   | 45   | 27   | 29   | 26   | 32   |
| with        | (    | (    | (    | (    | (    | (    | (    | (    |
| cortisol    | 100) | 100) | 100) | 100) | 100) | 100) | 100) | 100) |
| levels      |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| Pre-stim AM | 3    | 0    | 2    | 0    | 2    | 1    | 0    | 1    |
| cortisol    | (6)  | (0)  | (4)  | (0)  | (7)  | (3)  | (0)  | (3)  |
|             |      |      |      |      |      |      |      |      |
| \<4 mcg/dL  |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| Post-stim   | 2    | 7    | 5    | 4    | 3    | 1    | 4    | 3    |
| change      | (4)  | (13) | (10) | (9)  | (11) | (3)  | (15) | (9)  |
|             |      |      |      |      |      |      |      |      |
| \<5.6       |      |      |      |      |      |      |      |      |
| mcg/dL      |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| Post-stim   | 2    | 2    | 3    | 2    | 2    | 2    | 3    | 1    |
| cortisol    | (4)  | (4)  | (6)  | (4)  | (7)  | (7)  | (12) | (3)  |
|             |      |      |      |      |      |      |      |      |
| \<14.5      |      |      |      |      |      |      |      |      |
| mcg/dL      |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+

Mean cortisol levels for cosyntropin stimulation testing are displayed
in Table 11.3.24. Mean pre-stimulation cortisol levels were slightly
lower at Endpoint than at Day 1 for each of the treatment groups,
including the placebo group. Mean post-stimulation cortisol levels were
slightly lower for all treatment groups at Endpoint than at Day 1 for
all treatment groups except SAL 50/FP 250.

Table 11.3.24. Mean cortisol levels, pre-and post-cosyntropin
stimulation, SFCA3007 \[clinstat\\copd\\sfca3007.pdf, pages 965-966\].

+----------+------+------+------+------+------+------+------+------+
|          | Day  |      |      |      | Endp |      |      |      |
|          | 1    |      |      |      | oint |      |      |      |
+==========+======+======+======+======+======+======+======+======+
|          | Pbo  | SAL  | FP   | SAL  | Pbo  | SAL  | FP   | SAL  |
|          |      | 50   | 250  | 50/  |      | 50   | 250  | 50/  |
|          | N    |      |      | FP   | N    |      |      | FP   |
|          | =185 | N    | N    | 250  | =185 | N    | N    | 250  |
|          |      | =177 | =183 |      |      | =177 | =183 |      |
|          |      |      |      | N    |      |      |      | N    |
|          |      |      |      | =178 |      |      |      | =178 |
+----------+------+------+------+------+------+------+------+------+
| Pre-sti  | 1    | 1    | 1    | 1    | 1    | 1    | 1    | 1    |
| mulation | 2.43 | 2.98 | 1.56 | 3.40 | 1.13 | 2.24 | 0.55 | 2.38 |
| c        |      |      |      |      |      |      |      |      |
| ortisol, | (5   | (5   | (4   | (6   | (    | (7   | (3   | (5   |
| mcg/dL   | .57) | .12) | .07) | .76) | 5.59 | .05) | .63) | .72) |
|          |      |      |      |      |      |      |      |      |
| (SD)     |      |      |      |      |      |      |      |      |
+----------+------+------+------+------+------+------+------+------+
| Post-sti | 2    | 2    | 2    | 2    | 2    | 2    | 2    | 2    |
| mulation | 5.94 | 4.61 | 3.96 | 3.89 | 3.23 | 3.57 | 2.14 | 3.19 |
| c        |      |      |      |      |      |      |      |      |
| ortisol, | (6   | (5   | (5   | (6   | (6   | (7   | (6   | (4   |
| mcg/dL   | .57) | .18) | .69) | .12) | .83) | .60) | .79) | .38) |
|          |      |      |      |      |      |      |      |      |
| (SD)     |      |      |      |      |      |      |      |      |
+----------+------+------+------+------+------+------+------+------+
| Di       | 1    | 1    | 1    | 1    | 1    | 1    | 1    | 1    |
| fference | 3.51 | 1.63 | 2.40 | 0.49 | 2.10 | 1.33 | 1.59 | 0.81 |
| in       |      |      |      |      |      |      |      |      |
| means,   |      |      |      |      |      |      |      |      |
| pre-sti  |      |      |      |      |      |      |      |      |
| mulation |      |      |      |      |      |      |      |      |
| to       |      |      |      |      |      |      |      |      |
| po       |      |      |      |      |      |      |      |      |
| st-stimu |      |      |      |      |      |      |      |      |
| lation\* |      |      |      |      |      |      |      |      |
+----------+------+------+------+------+------+------+------+------+

\*Calculated from sponsor's data.

*[Reviewer comment:]{.underline}*

*The data for cosyntropin stimulation testing show no evidence of
adrenal suppression. It should be noted, however, that cosyntropin
stimulation testing is intended as a means to diagnose adrenal
insufficiency and is fairly insensitive as a measure of adrenal
suppression.*

##### Adverse events

Adverse events (AEs) were common in this study. These data are
summarized in Table 11.3.25. AEs were more common in FP 250 (70%,
129/177) and SAL 50/FP 250 (70%, 124/178) patients than for placebo
(64%, 118/185). AEs occurring at a frequency ≥3% and more frequently
with FP 250 or SAL 50/FP 250 than with placebo included headaches,
musculoskeletal pain, sinusitis, throat irritation, candidiasis of the
mouth/throat, viral respiratory infection, upper respiratory tract
inflammation, ear signs and symptoms, chest symptoms, sinusitis/sinus
infection, muscle injuries, hoarseness/dysphonia, fever, muscle cramps
and spasms, pain, epistaxis, edema and swelling, dizziness, nasal
congestion/blockage, and constipation \[clinstat\\copd\\sfca3007.pdf,
pages 155, 896-910\].

Many of the AEs noted are noted in the labels for Flovent MDI and
Flovent Rotadisk. These include upper respiratory tract infection,
headaches, musculoskeletal pain, sinusitis, candidiasis, viral
respiratory infections, muscle injuries, hoarseness/dysphonia, fever,
epistaxis, dizziness, and nasal congestion. AEs reported in this study
that are not noted in current labeling for other Flovent products
include ear signs and symptoms and muscle cramps and spasms. These may
represent new safety signals. It is difficult to assess whether other
AEs noted in this study that were not noted in current Flovent labeling
represent new safety signals because of their low frequencies.

*[Reviewer comment:]{.underline}*

*There were more patients with COPD exacerbations reported for the
secondary efficacy endpoint than were reported as AEs.*

Table 11.3.25. Adverse events occurring more frequently in FP 250 or SAL
50/FP 250 than in placebo and ≥3%, SCFA3007. Entries represent number
(percent) of patients \[clinstat\\copd\\sfca3007.pdf, pages 155,
896-910\].

+------------------------+--------------+--------------+--------------+
| **Adverse event**      | **Placebo**  | **FP 250**   | **SAL 50/FP  |
|                        |              |              | 250**        |
|                        | **N = 185**  | **N = 177**  |              |
|                        |              |              | **N = 178**  |
|                        | **n (%)**    | **n (%)**    |              |
|                        |              |              | **n (%)**    |
+========================+==============+==============+==============+
| All adverse events     | 118 (64)     | 129 (70)     | 124 (70)     |
+------------------------+--------------+--------------+--------------+
| Headaches              | 22 (12)      | 21 (11)      | 28 (16)      |
+------------------------+--------------+--------------+--------------+
| Musculoskeletal pain   | 16 (9)       | 14 (8)       | 16 (9)       |
+------------------------+--------------+--------------+--------------+
| Sinusitis              | 5 (3)        | 14 (8)       | 6 (3)        |
+------------------------+--------------+--------------+--------------+
| Throat irritation      | 13 (7)       | 10 (5)       | 15 (8)       |
+------------------------+--------------+--------------+--------------+
| Candidiasis            | 2 (1)        | 11 (6)       | 17 (10)      |
| mouth/throat           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Viral respiratory      | 6 (3)        | 8 (4)        | 10 (6)       |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Upper respiratory      | 6 (3)        | 7 (4)        | 4 (2)        |
| inflammation           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Ear signs and symptoms | 2 (1)        | 6 (3)        | 4 (2)        |
+------------------------+--------------+--------------+--------------+
| Muscle injuries        | 2 (1)        | 6 (3)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Hoarseness/dysphonia   | 0 (0)        | 5 (3)        | 9 (5)        |
+------------------------+--------------+--------------+--------------+
| Fever                  | 5 (3)        | 5 (3)        | 8 (4)        |
+------------------------+--------------+--------------+--------------+
| Muscle cramps and      | 2 (1)        | 5 (3)        | 6 (3)        |
| spasms                 |              |              |              |
+------------------------+--------------+--------------+--------------+
| Pain                   | 3 (2)        | 5 (3)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Epistaxis              | 2 (1)        | 5 (3)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Edema and swelling     | 2 (1)        | 3 (2)        | 5 (3)        |
+------------------------+--------------+--------------+--------------+
| Dizziness              | 3 (2)        | 1 (\<1)      | 7 (4)        |
+------------------------+--------------+--------------+--------------+
| Nasal                  | 4 (2)        | 1 (\<1)      | 5 (3)        |
| congestion/blockage    |              |              |              |
+------------------------+--------------+--------------+--------------+
| Constipation           | 4 (2)        | 1 (\<1)      | 5 (3)        |
+------------------------+--------------+--------------+--------------+

AEs beginning after a patient discontinued study medication were
infrequent and occurred at similar frequencies in active treatment
groups and placebo \[clinstat\\copd\\sfca3007.pdf, page 156\]. The
highest incidence of AEs was in the first month of treatment (35%
placebo, 44% FP 250, 41% SAL 50/FP 250). The most common-drug related
AEs included candidiasis of the mouth or throat, headaches, throat
irritation, and hoarseness/dysphonia \[clinstat\\copd\\sfca3007.pdf,
page 157\].

A listing of AEs of low frequency is found in Table 11.3.26. This
listing includes AEs that have been associated with use of
corticosteroids, such as candidiasis, and hoarseness/dysphonia,
infection. Candidiasis of the mouth/throat, viral respiratory
infections, hoarseness/dysphonia, candidiasis of unspecified site,
pharyngitis/throat infection, and laryngitis, were more frequent in FP
250 and SAL 50/FP 500-treated patients than in placebo. The frequency of
fractures was similar among treatment groups. Although there were no AEs
reported as diabetes mellitus, hyperglycemia was noted only in the FP
250 and SAL 50/FP 250 groups. One patient treated with SAL 50/FP 250,
Patient #17781, was reported as having polyuria and diuresis, but was
not one of the patients who was reported as having hyperglycemia,
\[clinstat\\copd\\sfca3007.pdf, page 5749\].

There were no cases of osteoporosis noted in the FP 250 and SAL 50/FP
250 groups, and there were no cases of cataract, glaucoma, or increased
intraocular pressure in any of the treatment groups. It should be noted
however that neither formal ophthalmologic examination nor bone
densitometry were used to specifically look for these AEs. Small numbers
of other AEs were observed without a strong association with FP 250 or
SAL 50/FP 250 \[clinstat\\copd\\sfca3007.pdf, pages 896-910\].

Table 11.3.26. Selected adverse events of low frequency, SFCA3007.
Entries represent number (percent) of patients
\[clinstat\\copd\\sfca3007.pdf, pages 896-910\].

+------------------------+--------------+--------------+--------------+
| **Adverse event**      | **Placebo**  | **FP 250**   | **SAL5 50/FP |
|                        |              |              | 250**        |
|                        | **N = 185**  | **N = 183**  |              |
|                        |              |              | **N = 178**  |
|                        | **n (%)**    | **n (%)**    |              |
|                        |              |              | **n (%)**    |
+========================+==============+==============+==============+
| All adverse events\*   | 118 (64)     | 129 (70)     | 124 (70)     |
+------------------------+--------------+--------------+--------------+
| Candidiasis            | 2 (1)        | 11 (6)       | 17 (10)      |
| mouth/throat           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Viral respiratory      | 6 (3)        | 8 (4)        | 10 (6)       |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Hoarseness/dysphonia   | 0 (0)        | 5 (3)        | 9 (5)        |
+------------------------+--------------+--------------+--------------+
| Candidiasis            | 0 (0)        | 4 (2)        | 3 (2)        |
| unspecified site       |              |              |              |
+------------------------+--------------+--------------+--------------+
| Dental discomfort &    | 2 (1)        | 4 (2)        | 1 (\<1)      |
| pain                   |              |              |              |
+------------------------+--------------+--------------+--------------+
| Pharyngitis/throat     | 1 (\<1)      | 3 (2)        | 4 (2)        |
| infection              |              |              |              |
+------------------------+--------------+--------------+--------------+
| Contusions and         | 2 (1)        | 3 (2)        | 2 (1)        |
| hematomas              |              |              |              |
+------------------------+--------------+--------------+--------------+
| Gastrointestinal       | 2 (1)        | 3 (2)        | 2 (1)        |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Anxiety                | 3 (2)        | 3 (2)        | 1.  \(1\)    |
+------------------------+--------------+--------------+--------------+
| COPD                   | 1 (\<1)      | 3 (2)        | 2.  \(0\)    |
+------------------------+--------------+--------------+--------------+
| Viral infections       | 2 (1)        | 2 (1)        | 4 (2)        |
+------------------------+--------------+--------------+--------------+
| Hypertension           | 5 (3)        | 2 (1)        | 4 (2)        |
+------------------------+--------------+--------------+--------------+
| Fractures              | 3 (2)        | 2 (1)        | 3 (2)        |
+------------------------+--------------+--------------+--------------+
| Abnormal liver         | 1 (\<1)      | 2 (1)        | 2 (1)        |
| function tests         |              |              |              |
+------------------------+--------------+--------------+--------------+
| Hyperglycemia          | 0 (0)        | 2 (1)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Viral skin infections  | 3 (2)        | 2 (1)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Depressive disorders   | 3 (2)        | 2 (1)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Pneumonia              | 0 (0)        | 2 (1)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Gum signs and symptoms | 1 (\<1)      | 2 (1)        | 1.  (\<1)    |
+------------------------+--------------+--------------+--------------+
| Laryngitis             | 0 (0)        | 1 (\<1)      | 4 (2)        |
+------------------------+--------------+--------------+--------------+
| Urinary infections     | 4 (2)        | 1 (\<1)      | 3 (2)        |
+------------------------+--------------+--------------+--------------+
| Eye infections         | 1 (\<1)      | 1 (\<1)      | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Situational disorders  | 1 (\<1)      | 1 (\<1)      | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Hypokalemia            | 0 (0)        | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Hypoglycemia           | 1 (\<1)      | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Psychogenic disorders  | 0 (0)        | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Fungal reproductive    | 0 (0)        | 1 (\<1)      | 0 (0)        |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Fungal infection mouth | 0 (0)        | 1 (\<1)      | 0 (0)        |
| and throat             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Viral gastrointestinal | 1 (\<1)      | 1 (\<1)      | 0 (0)        |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Tooth decay            | 1 (\<1)      | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Dental operations      | 0 (0)        | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Gastroenteritis        | 0 (0)        | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Increased blood        | 1 (\<1)      | 1 (\<1)      | 0 (0)        |
| pressure               |              |              |              |
+------------------------+--------------+--------------+--------------+
| Nocturia               | 0 (0)        | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Purpura                | 0 (0)        | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Ear, nose, and throat  | 0 (\<1)      | 0 (0)        | 3 (2)        |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Fungal skin infections | 2 (1)        | 0 (0)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Bacterial infections   | 1 (\<1)      | 0 (0)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Lower respiratory      | 2 (1)        | 0 (0)        | 2 (1)        |
| hemorrhage             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Musculoskeletal        | 0 (0)        | 0 (0)        | 1 (\<1)      |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+
| Agitation              | 1 (\<1)      | 0 (0)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Disorders of hard      | 2 (1)        | 0 (0)        | 1 (\<1)      |
| tissues of teeth       |              |              |              |
+------------------------+--------------+--------------+--------------+
| Polyuria and diuresis  | 0 (0)        | 0 (0)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Increased white cells  | 0 (0)        | 0 (0)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Skin infections        | 1 (\<1)      | 0 (0)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Viral eye infections   | 0 (0)        | 0 (0)        | 1.  (\<1)    |
+------------------------+--------------+--------------+--------------+
| Electrolyte            | 0 (0)        | 0 (0)        | 1.  (\<1)    |
| disturbances           |              |              |              |
+------------------------+--------------+--------------+--------------+
| Osteoporosis           | 1 (\<1)      | 0 (0)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Infections             | 1 (\<1)      | 0 (0)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Bacterial skin         | 1 (\<1)      | 0 (0)        | 0 (0)        |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+

Subgroup analysis of AEs by gender, age, and race will be reviewed in
the Integrated Review of Safety section of this document.

*[Reviewer comment:]{.underline}*

*The high frequency of oropharyngeal thrush in the groups receiving FP
is worth noting and may be indicative of a more globally
immunosuppressed condition. There were a few patients reported as having
"contusions and hematomas," and one patient was reported to have
"purpura." Otherwise, there were no other patients who were reported as
having bruising. One would expect a fairly significant number of
patients to have had this AE, given the large doses of FP used and given
the older ages of the patients studied. Unfortunately this study was not
designed to specifically look for cataract or systemic bone effects,
both known to be associated with systemic effects of corticosteroids.
Ophthalmologic examination and studies to assess osteoporosis would have
been helpful to address these concerns. It is notable that hyperglycemia
was noted only in the FP 250 and SAL 50/FP 250 groups, and not in the
placebo group. Hyperglycemia is likely to represent a safety signal for
the FP 250 and SAL 50/FP 250 groups.*

##### Deaths and serious adverse events

There were no deaths that occurred during the study
\[clinstat\\copd\\sfca3007.pdf, page 158\].

There were 34 patients (34/723) who experienced a serious adverse event
(SAE) during the treatment phase of the study. The percentage of
patients was SAEs during the treatment phase were similar among the
treatment groups, with the highest in the placebo group (6%, 11/185),
followed by FP 250 (5%, 10/183), and SAL 50/FP 250 (4%, 8/178). SAEs
occurring in more than one patient are displayed in Table 11.3.27. SAL
50-treated patients are not represented in this table. SAEs due to
chronic obstructive airways disease were most frequent in FP 250 (3%,
2/183) compared with placebo (\<1%, 1/185) and SAL 50/FP 250 (0%,
0/178). Chest symptoms (literal term "chest pain") occurred in equal at
fairly similar frequencies among treatment groups. Cholelithiasis
occurred most frequently in FP 250 (1%, 2/183), followed by placebo
(\<1%, 1/185), and SAL 50/FP 250 (0%, 0/178). Cholecystitis occurred at
similar frequencies in FP 250 (\<1%, 1/183) and SAL 50/250 (\<1%,
1/178). One FP 250 patient, #13964, was reported as having both
cholelithiasis and cholecystitis \[clinstat\\copd\\sfca3007.pdf, page
5764\].

Table 11.3.27. SAEs occurring in more than one patient during the
treatment period, SFCA3007 \[clinstat\\copd\\sfca3007.pdf, pages 159,
1411-1413\].

+------------------------+--------------+--------------+--------------+
| **Serious adverse      | **Placebo**  | **FP 250**   | **SAL 50/FP  |
| event**                |              |              | 250**        |
|                        | **N = 185**  | **N = 183**  |              |
|                        |              |              | **N = 178**  |
|                        | **n (%)**    | **n (%)**    |              |
|                        |              |              | **n (%)**    |
+========================+==============+==============+==============+
| Any serious adverse    | 11 (6)       | 10 (5)       | 8 (4)        |
| event                  |              |              |              |
+------------------------+--------------+--------------+--------------+
| Chronic obstructive    | 1 (\<1)      | 3 (2)        | 0 (0)        |
| airways disease        |              |              |              |
+------------------------+--------------+--------------+--------------+
| Cholelithiasis         | 1 (\<1)      | 2 (1)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Chest symptoms\*       | 2 (1)        | 0 (0)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Cholecystitis          | 0 (0)        | 1 (\<1)      | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+
| Fractures              | 1 (\<1)      | 0 (0)        | 1 (\<1)      |
+------------------------+--------------+--------------+--------------+

\*All events coded as chest symptoms were due to chest pain.

There was one patient each in the SAL 50/FP 250 group and placebo group
that had a SAE for fracture. The SAL 50/FP 250 patient, #16741, was a 58
year-old female who fractured her femur due to a fall. This patient
withdrew from the study \[clinstat\\copd\\sfca3007.pdf, pages 160,
5769\]. The placebo patient, #13531, a 57 year-old man who sustained
fractured ribs and a chest contusion in an auto accident. This patient
continued in the study \[clinstat\\copd\\sfca3007.pdf, pages 160,
5753\].

*[Reviewer comment:]{.underline}*

*The higher frequency of SAEs for COPD in the FP 250 group is
interesting, as there was a higher frequency of SAEs for COPD and
pneumonia in the FP 500 and SAL 50/FP 500 groups in SFCA3006. It is also
interesting that the only hip fracture occurred in a FP 250-treated
patient. Although this SAE could be drug-related, a woman of this age
would also be at a higher risk for fracture from pre-existing
osteoporosis.*

##### Withdrawals due to adverse events

Withdrawals due to adverse events (AEs) are displayed in Table 11.3.28.
Withdrawals due to AEs occurred at similar frequencies for FP 250 (5%,
10/183), SAL 50/FP 250 (5%, 9/178), and placebo (4%, 8/185). Withdrawals
due to COPD were most common in the FP 250 group (2%, 2/183), followed
by the placebo group (\<1%, 1/185) and the SAL 50/FP 500 group (0%,
0/178). There were two withdrawals due to fractures, and both patients
were in the SAL 50/FP 250 group. Patient #16636 was a 79 year-old woman
who fractured three ribs in an auto accident
\[clinstat\\copd\\sfca3007.pdf, pages 160, 5785;
crf\\sfca3007\\66\\p0016636.pdf, page 1\]. Patient #16741 was a 58
year-old woman who fell on her flexed left knee and fractured the
supracondylar and intercondylar areas of her femur in a fall
\[clinstat\\copd\\sfca3007.pdf, pages 160, 5785;
crf\\sfca3007\\68\\p0016741.pdf, page 1, NDA 20-833, SE1 004 C, 12/3/01,
page 5\].

Table 11.3.28. Withdrawals due to adverse events occurring in more than
one patient, SFCA3007 \[clinstat\\copd\\sfca3007.pdf, page 161\].

+------------------------+--------------+--------------+--------------+
| **Adverse event**      | **Placebo**  | **FP 250**   | **SAL 50/FP  |
|                        |              |              | 250**        |
|                        | **N = 185**  | **N = 183**  |              |
|                        |              |              | **N = 178**  |
|                        | **n (%)**    | **n (%)**    |              |
|                        |              |              | **n (%)**    |
+========================+==============+==============+==============+
| Any adverse event      | 8 (4)        | 10 (5)       | 9 (5)        |
+------------------------+--------------+--------------+--------------+
| Chronic obstructive    | 1 (\<1)      | 3 (2)        | 0 (0)        |
| airways disease        |              |              |              |
+------------------------+--------------+--------------+--------------+
| Fractures              | 0 (0)        | 0 (0)        | 2 (1)        |
+------------------------+--------------+--------------+--------------+
| Depressive disorders   | 2 (1)        | 0 (0)        | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Pneumonia              | 0 (0)        | 1 (\<1)      | 0 (0)        |
+------------------------+--------------+--------------+--------------+
| Malignant breast       | 1 (\<1)      | 0 (0)        | 1 (\<1)      |
| neoplasia              |              |              |              |
+------------------------+--------------+--------------+--------------+
| Viral respiratory      | 0 (0)        | 1 (\<1)      | 1 (\<1)      |
| infections             |              |              |              |
+------------------------+--------------+--------------+--------------+

*[Reviewer comment:]{.underline}*

*Withdrawals due to COPD were most common in the FP 250 group, a pattern
seen with SAEs in this study and with FP 500 in SFCA3006.*

##### Vital signs

There were no clinically significant changes from baseline in median
values of vital signs for any of the treatment groups
\[clinstat\\copd\\sfca3007.pdf, pages 999-1004\].

##### Physical examination

Physical examinations were performed at Screening and at the end of the
study \[clinstat\\copd\\sfca3007.pdf, page 64\]. Data was recorded on
subject progress notes, but not on case report forms (CRFs). Physical
examination abnormalities were recorded as AEs on the CRFs, but no
summary of physical examinations was provided \[NDA 20-833, SE1-004, BM,
9/17/01, page 3\].

##### Oropharyngeal examination

Oropharyngeal examinations were performed at each treatment visit, every
treatment visit, and at the end of the study
\[clinstat\\copd\\sfca3007.pdf, page 64\]. Data was recorded on subject
progress notes, but not on case report forms (CRFs). Oropharyngeal
examination abnormalities were recorded as AEs on the CRFs, but no
summary of oropharyngeal examinations was provided \[NDA 20-833,
SE1-004, BM, 9/17/01, page 2\].

##### Laboratory studies

Shifts in hematology studies from baseline at Weeks 12 and 24 were
similar among treatment groups \[clinstat\\copd\\sfca3007.pdf, pages
162, 923-933\].

There was a higher proportion of patients in the SAL 50/FP 250 (22%) and
SAL 50 (15%) groups that had a shift in lymphocyte count to low at the
Discontinuation visit as compared with the placebo (10%) and FP 250 (3%)
groups \[clinstat\\copd\\sfca3007.pdf, pages 162, 923-933\].

There was a higher proportion of patients in the SAL 50/FP 250 (20%) and
SAL 50 (17%) groups that had a shift in neutrophil count to high at the
Discontinuation visit as compared with the placebo (12%) and FP 250 (0%)
groups \[clinstat\\copd\\sfca3007.pdf, pages 162, 923-933\].

There was a higher proportion of patients in the FP 250 (18%), SAL 50
(17%), and FP 250 (18%) groups that had a shift in WBC count to high at
the Discontinuation visit as compared with the placebo (10%) group
\[clinstat\\copd\\sfca3007.pdf, pages 162, 923-933\].

There was no meaningful difference between treatment groups in the
percentage of patients who had increases from baseline in glucose at
Week 12, Week 24, and Discontinuation \[clinstat\\copd\\sfca3007.pdf,
pages 163, 934-942\]. However, it should be noted that the sponsor
defined an exceptionally liberal definition for high glucose, \>175
mg/ml. It is likely that this liberal definition of high glucose would
decrease the sensitivity of detecting a difference between treatment
groups for this laboratory test \[clinstat\\copd\\sfca3007.pdf, page
5787\].

There was a higher proportion of patients in the SAL 50/FP 250 group
(12%) that had a shift in ALT to high at the Discontinuation visit as
compared with the placebo (6%), SAL 50 (4%), and FP 250 (5%) groups
\[clinstat\\copd\\sfca3007.pdf, pages 162, 923-933\].

There was a higher proportion of patients in the FP 250 (3%) and SAL
50/FP 250 (4%) groups that had a shift in alkaline phosphatase to high
at Week 12, compared with the placebo (2%), SAL 50 (\<1%), and FP 250
(5%) groups. This was not noted at the 24 Week visit, but was noted at
the Discontinuation visit, with the largest shifts of alkaline
phosphatase in the SAL 50/FP 250 (7%) and FP 250 (3%) groups, compared
with placebo (0%) and SAL 50 (2%) \[clinstat\\copd\\sfca3007.pdf, pages
162, 923-933\].

There were no meaningful differences among treatment groups in the
percentage of patients with changes in other laboratory studies
\[clinstat\\copd\\sfca3007.pdf, pages 162, 923-933\].

*[Reviewer comment:]{.underline}*

*The higher percentage of patients with decrease in % lymphocytes, and
increases in WBC and % neutrophils in FP 500 and SAL 50/FP 500 at the
Discontinuation visit could be a manifestation of a systemic
corticosteroid effect. This effect was not noted at Weeks 12 or 24, and
could be a manifestation COPD, the most common reason for
discontinuation in all treatment groups.*

*The lack of a noted effect in shifts of glucose is much less reassuring
because of the high value chosen as a definition for elevated glucose.
Changes alkaline phosphatase could represent liver or bone effects of
FP, but also may be a chance occurrence.*

There were few patients with hematology or chemistry results outside of
values specified as normal by the sponsor. The few patients with results
outside of the range specified as normal by the sponsor were evenly
distributed between treatment groups \[clinstat\\copd\\sfca3007.pdf,
pages 953-964\].

*[Reviewer comment:]{.underline}*

*As with shifts in glucose, the lack of difference between treatment
groups in the percentage of patients with elevated glucose is much less
reassuring because of the high value chosen as the definition.*

##### ECGs

There were more patients with clinically significant changes in ECGs
from baseline in the placebo group at Week 12 (\<1%, 1/135), Week 24
(2%, 2/121), and Discontinuation (4%, 2/49), than FP 250 and SAL 50/FP
250 groups (0%, 0 patients at each of the visits)
\[clinstat\\copd\\sfca3007.pdf, page 167\].

There were five clinically significant changes in ECGs from baseline in
four patients in the placebo group. There were no clinically significant
changes in ECGs from baseline for FP 250 or SAL 50/FP 250 groups
\[clinstat\\copd\\sfca3007.pdf, pages 167, 979-984\].

Median QTc intervals by both Bazette and Fridericia formulae were
similar for each of the treatment groups, as was the percentage of
patients with change from baseline in QTc intervals
\[clinstat\\copd\\sfca3007.pdf, pages 169-170, 985-992\]. Two patients
in the placebo group, one patient in the FP 500 group, and two patients
in the SAL 50/FP 250 group had QTcB \>470 msec at Weeks 12, 24, and
Discontinuation \[clinstat\\copd\\sfca3007.pdf, page 171\].

*[Reviewer comment:]{.underline}*

*Review of ECG results reveals no evidence of a safety signal for FP in
the population studied.*

### References

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7.  Rubin BK, Ramirez O, Ohar JA. Iodinated glycerol has no effect on
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9.  Anthionisen NR, Manfreda J, Warren CPW, et. al. Antibiotic therapy
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    Med 1987;106:196-204

10. Guyatt GH, Berman LB, Townsend M, et. al. A measure of quality of
    life for clinical trials in chronic lung diseases. Thorax
    1987;42:773-778

11. Pulmicort package insert. Astra Inc., USA. Westborough, MA October
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Reviewed by:

­­­­­\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Charles E. Lee, M.D.

Medical Officer, Division of Pulmonary and Allergy Drug Products

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Mary Purucker, M.D., Ph.D.

Team Leader, Division of Pulmonary and Allergy Drug Products

cc: Original NDA

HFD-570/Division File

> HFD-570/Purucker/Medical Team Leader
>
> HFD-570/Lee/Medical Reviewer
>
> HFD-870/Suarez/Biopharmaceutics Reviewer

HFD-570/Jafari/Project Manager

HFD-570/Gilbert-McClain/Medical Officer

HFD-570/Sullivan/Medical Officer

[^1]: Effect size = [(mean change from Baseline in FEV1, active) minus
    (mean change from Baseline in FEV1, Pbo)]{.underline}

    Baseline FEV1, active

[^2]: Effect size = [(mean change from Baseline in FEV~1~, FP 500) minus
    (mean change from Baseline in FEV~1~, Pbo)]{.underline}

    Baseline FEV~[1]{.underline}~, FP 500

[^3]: ^1^ Effect size = [(mean change from Baseline in FEV~1~, FP 250)
    minus (mean change from Baseline in FEV~1~, Pbo)]{.underline}

    Baseline FEV~1~, FP 250