24 June 2003 Arthritis Advisory Committee Meeting

Briefing Document for ENBRELâ (etanercept)

For the Treatment of Ankylosing Spondylitis

28 May 2003

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799


Table of Contents

1.                     Executive Summary.................................................................... 1

1.1                   Background and Rationale............................................................ 1

1.2                   Clinical Development of Etanercept for the Treatment of Patients with Ankylosing Spondylitis.................................................................. 1

1.3                   Summary of Efficacy.................................................................... 1

1.4                   Summary of Safety...................................................................... 2

1.5                   Conclusion.................................................................................. 2

2.                     Rationale for Etanercept use in the Treatment of Ankylosing Spondylitis................................................................................. 3

2.1                   Etanercept Background................................................................ 3

2.2                   Ankylosing Spondylitis.................................................................. 3

2.2.1                 Description of the Disease Setting................................................. 3

2.2.2                 Description of Currently Available Therapies................................... 4

2.2.3                 Role of Tumor Necrosis Factor in Ankylosing Spondylitis................. 4

3.                     Development of Disease Response Criteria in Ankylosing Spondylitis................................................................................. 4

3.1                   Ankylosing Spondylitis Assessment (ASAS) Working Group Criteria 4

3.2                   Disease Controlling Anti-Rheumatic Therapy (DCART).................... 6

4.                     Description of the Etanercept Development Program for Ankylosing Spondylitis............................................................... 7

4.1                   Overview of the Program............................................................... 7

4.2                   Proof of Principle (Study 16.0626)................................................ 7

4.3                   Pivotal Program............................................................................ 8

4.3.1                 Study Designs............................................................................. 8

4.3.2                 Study Endpoints........................................................................... 9

4.4                   Statistical Analyses..................................................................... 10

5.                     Results for Pivotal Program..................................................... 11

5.1                   Study Populations....................................................................... 11

5.1.1                 Baseline Demographics and Disease Characteristics.................... 11

5.1.2                 Study Completion....................................................................... 14

5.2                   Efficacy Results......................................................................... 14

5.2.1                 Primary Endpoint:  Protocol-Defined ASAS Response................... 14

5.2.2                 Individual Components of ASAS 20.............................................. 17

5.2.3                 Additional Measures of Disease Activity....................................... 19

5.2.4                 Disease-Controlling Anti-Rheumatic Therapy Response................. 21

5.2.5                 Subgroup Analyses for Study 016.0037....................................... 22

5.3                   Summary of Efficacy Results...................................................... 23

6.                     Safety Results.......................................................................... 24

6.1                   Overview of Safety Results.......................................................... 24

6.2                   Serious Adverse Events.............................................................. 24

6.3                   Medically Important Infections..................................................... 25

6.4                   Withdrawals Because of Adverse Events...................................... 25

6.5                   Noninfectious Adverse Events...................................................... 26

6.6                   Infections................................................................................... 27

6.7                   Malignancies.............................................................................. 28

6.8                   Clinical Laboratory Results.......................................................... 28

6.9                   Antibody Results......................................................................... 29

6.10                  Safety Summary and Conclusions............................................... 29

6.11                  Safety Profile in Ankylosing Spondylitis is Comparable to Established Etanercept Safety Profile in Rheumatic Diseases.......................... 30

6.11.1               Clinical Trials in Subjects with Rheumatoid Arthritis and Psoriatic Arthritis...................................................................................... 30

6.11.2               Comparison of Etanercept Safety Results in Ankylosing Spondylitis with Rheumatoid Arthritis and Psoriatic Arthritis Populations........... 30

7.                     Risk-Benefit Assessment.......................................................... 31

8.                     References............................................................................... 32

 

List of Tables

Table 3‑1.  Ankylosing Spondylitis Assessment Group Preliminary Definition of Short-Term Improvement in Ankylosing Spondylitis (Anderson et al, 2001). 6

Table 4‑1.  Study 16.0626:  Efficacy Results at Week 16........................................ 8

Table 5‑1.  Baseline Demographics and Therapy in the Pivotal Program................. 12

Table 5‑2.  Baseline Disease Characteristics in the Pivotal Program....................... 13

Table 5‑3.  Study 016.0037:  Primary Endpoint:   ASAS 20 at Weeks 12 and 24..... 16

Table 5‑4.  Study 016.0037:  Secondary Endpoints:   ASAS 50 and 70, and Partial Remission at Weeks 12 and 24................................................... 16

Table 5‑5.  Study 47687.  Primary and Secondary Endpoints: ASAS 20, 50, 70, and Partial Remission at Week 12...................................................... 18

Table 5‑6.  Study 016.0037:  Results for Individual Components of Protocol‑Defined ASAS 20................................................................................... 19

Table 5‑7.  Study 47687:  Results for Individual Components of the Protocol‑Defined ASAS 20 at Week 12.................................................................. 19

Table 5‑8.  Study 016.0037:  Results for BASDAI, Spinal Mobility, Acute Phase Reactants, Assessor Global, and Peripheral Joint Counts.............. 21

Table 5‑9.  Study 47687:  Results for BASDAI, Spinal Mobility, Acute Phase Reactants, and Assessor Global at Week 12................................. 22

Table 5‑10.  Study 016.0037: DCART 20 and DCART 40 Responses...................... 23

Table 6‑1.  Overall Summary of Adverse Events in Studies 016.0037 and 47687: Number (%) of Subjects Reporting Adverse Events....................... 25

Table 6‑2.  Study 016.0037:  Summary of Serious Adverse Events......................... 26

Table 6‑3.  Study 016.0037:  Summary of Adverse Events Causing Withdrawal....... 27

Table 6‑4.  Noninfectious Adverse Events in ³ 5% of Subjects in Either Study or Treatment Group................................................. 28

Table 6‑5.  Infections in ³ 5% of Subjects in Either Study or Treatment Group......... 29

 

List of Figures

Figure 5‑1.  Study 016.0037:  Percent of Subjects Achieving Protocol-Defined ASAS 20, 50, and 70 Over Time............................................................ 17

 


1.                                   Executive Summary

1.1                                Background and Rationale

Ankylosing spondylitis (AS) is a chronic disease characterized by ankylosis of the spine, inflammation at the insertions of tendons, and occasionally peripheral arthritis.  AS occurs predominantly in men, with onset before age 30, and produces pain and stiffness as a result of inflammation of the sacroiliac, intervertebral, and costovertebral joints.  The disease afflicts approximately 350,000 patients in the United States (Carter et al, 1979).

The only approved therapies for AS are nonsteroidal anti-inflammatory agents (NSAIDs) (Toussirot and Wendling, 1998).  These therapies reduce symptoms but have no demonstrated effect on the progressive, debilitating spinal immobility that is a hallmark of the disease.  Second-line therapies, typically borrowed from the armamentarium for rheumatoid arthritis (RA), have demonstrated little effect or have been poorly studied.  There is clearly a need for improved therapies for this disease.

There is accumulating evidence that tumor necrosis factor (TNF) plays an important role in AS, suggesting that anti-TNF therapies such as etanercept could offer benefits not provided by current therapies.  The clinical data reviewed in this briefing package demonstrate that etanercept has the potential to be a significant therapeutic advance in the treatment of AS.

1.2                                Clinical Development of Etanercept for the Treatment of Patients with Ankylosing Spondylitis

The AS clinical development program evaluated etanercept 25 mg twice weekly in 401 subjects in 3 randomized, double-blind, placebo-controlled studies.  A proof-of-principle study evaluated etanercept in 40 AS subjects for 4 months.  The results showed improvement in multiple parameters of disease activity, including spinal mobility measures (Gorman et al, 2002).  Based on these data, Amgen initiated a 24-week study of 277 subjects with AS (Protocol 016.0037) and Wyeth initiated a similar 12-week study of 84 subjects (Study 0881A3-311-EU CSR 47687, hereafter referred to as Study 47687).

1.3                                Summary of Efficacy

The efficacy of etanercept in subjects with AS is compelling.  The positive findings in the proof-of-principle study were confirmed in a phase 3 study, Study 016.0037, where statistically significant responses for etanercept were seen as early as 2 weeks and sustained at 12 and 24 weeks.  The primary composite efficacy endpoint at week 12 was achieved by 60% of etanercept-treated patients compared with 27% of placebo patients (p < 0.0001). Sustained improvements were apparent in each component of the composite criteria, including inflammatory symptoms and patient physical function, and in measures of spinal mobility and acute phase reactants.  The efficacy of etanercept in AS was again clearly demonstrated in a supportive study, Study 47687. 

1.4                                Summary of Safety

Etanercept was well tolerated by subjects with AS.    Etanercept was associated with a higher incidence of injection site reactions, upper respiratory infections, and injury accidents than placebo.  Few significant laboratory abnormalities were observed in these studies.  Overall, the safety profile of etanercept in subjects with AS is similar to that observed in subjects with RA and psoriatic arthritis (PsA). 

1.5                                Conclusion

Three randomized, double-blind, placebo-controlled trials demonstrate that etanercept is effective in the treatment of subjects with AS, providing improvement in functional ability, spinal mobility, and acute-phase reactants.  Etanercept is well tolerated in this patient population with a safety profile similar to that observed in etanercept clinical trials with other inflammatory rheumatic diseases.  The risk benefit profile of etanercept in treating AS subjects is highly favorable.  Based on these data, the following addition is proposed for inclusion in the etanercept product label:

Etanercept is indicated for reducing signs and symptoms of active ankylosing spondylitis.

2.                                   Rationale for Etanercept use in the Treatment of Ankylosing Spondylitis

2.1                                Etanercept Background

Etanercept (ENBRELâ) is a fully human dimer of 2 molecules of the extracellular portion of the p75 tumor necrosis factor receptor (TNFR) fused to the Fc portion of a type 1 human immunoglobulin (IgG1).  Etanercept binds both TNF and lymphotoxin alpha (LTa) with high affinity.

Etanercept has been approved in the United States for reducing signs and symptoms and inhibiting the progression of structural damage in subjects with moderately to severely active RA; for reducing signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis (JRA) in subjects who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs); and for reducing signs and symptoms of active arthritis in subjects with psoriatic arthritis (PsA). 

Etanercept has been administered to 3389 subjects in rheumatic disease clinical trials for currently approved indications and the postmarketing worldwide commercial experience with etanercept includes more than 180,000 patients.  Clinical trials in RA have shown that etanercept remains safe and effective for over 6 years and allows subjects to reduce or discontinue the use of concomitant corticosteroids or methotrexate while maintaining clinical response.

2.2                                Ankylosing Spondylitis

2.2.1                           Description of the Disease Setting

Ankylosing spondylitis (as) is a chronic inflammatory arthritis and enthesopathy involving the spine and peripheral joints.  It occurs predominantly in men, with onset typically before age 30, and is associated with pain and stiffness resulting from inflammation of the sacroiliac, intervertebral, and costovertebral joints.  It is one of the spondyloarthropathies (SpA) marked by absence of plasma rheumatoid factor and an association with HLA‑B27.  These diseases also include psoriatic arthritis (PsA), reactive arthritis (ReA), and arthritis associated with inflammatory bowel disease.

The prevalence of SpA is estimated to be 0.6% to 1.9% and is similar to the prevalence of RA (0.8%) (Braun and Sieper, 2002).  It is estimated that there are currently over 350,000 AS patients in the United States (Carter et al, 1979).

A recent study showed that the degree of pain and disability among patients with AS is similar to that among patients with rheumatoid arthritis (Zink et al, 2000).  Moreover, many patients with AS have severe inflammatory symptoms even decades after diagnosis of the disease (Ward, 1999; Gran and Skomsvoll, 1997; Kennedy et al, 1993; Goodacre et al, 1991; Ringsdal and Andreasen, 1989; Taylor et al, 1998).

2.2.2                           Description of Currently Available Therapies

Traditional therapies, including NSAIDs, corticosteroids, and DMARDs, are inadequate for AS patients (Toussirot and Wendling, 1998).  NSAIDs are often used for symptomatic relief but may not control disease activity and appear incapable of effecting the progressive spinal immobility that is characteristic of AS (Toussirot and Wendling, 1998).  Sulfasalazine, while somewhat effective in treating peripheral arthritis, does little for axial disease (Dougados et al, 1995).  A small controlled study of methotrexate demonstrated no effect on AS (Roychowdhury et al, 2001).  In small studies, azathioprine showed some benefit in the treatment of ReA (Creemers et al, 1994). D-penicillamine, cyclophosphamide, levamisole, and methylprednisolone have yielded conflicting results (Creemers et al, 1994).  Oral gold, corticotropin, or antimalarials are not effective in AS (Amor 1995; Creemers et al, 1994).  Radiation treatment for synovitis has been abandoned because of its serious long-term side effects (Creemers et al, 1994).  Treatment options for SpA are extremely limited. 

2.2.3                           Role of Tumor Necrosis Factor in Ankylosing Spondylitis

Tumor necrosis factor (TNF) plays a major role in the pathogenesis of AS.  TNF levels are elevated in serum (Toussirot and Wendling, 1994, Gratacos 1994) and in synovial tissue (Canete et al, 1997; Grom et al, 1996) of patients with AS.  These findings suggested that interfering with the pro-inflammatory effects of TNF could reduce the clinical signs and symptoms of AS and improve quality of life for patients with AS.  As a result, Amgen initiated a clinical program to investigate the potential of etanercept as a new treatment for AS.

3.                                   Development of Disease Response Criteria in Ankylosing Spondylitis

3.1                                Ankylosing Spondylitis Assessment (ASAS) Working Group Criteria

AS is a systemic inflammatory disease that manifests variable clinical signs and symptoms.  Assessment of patient status and response to treatment has been problematic.  Since no disease-altering therapies were historically available, patients and physicians learned to accommodate to progressive debility from AS by addressing the symptoms related to pain and inflammation.  Definitive measures of AS had not been developed to assess the fundamental aspects of disease course. 

To address the need for an effective clinical outcome measure optimal for studying new therapeutic agents, the Ankylosing Spondylitis Assessment (ASAS) Working Group was organized.  This independent group of AS experts has been meeting for approximately 8 years, and their efforts toward establishing new AS assessment criteria have been published in peer-reviewed journals (Anderson et al, 2001; van der Heijde et al, 1999; van der Heijde et al, 1997). 

After considering over 100 potential clinical outcome measures, ASAS identified a core set of 5 clinical domains considered essential for characterizing changes in AS: physical function, pain, spinal mobility, patient global assessment, and inflammation.  Using data from clinical trials of NSAIDs in the treatment of AS to validate potential candidate response criteria from the 5 clinical domains, ASAS Working Group developed the Ankylosing Spondylitis Assessment Group Preliminary Definition of Short-Term Improvement in Ankylosing Spondylitis (ASAS 20), that included 4 of the 5 domains (Table 31 and Appendix 1) and specified instruments for measuring them.  Spinal mobility was not included in the ASAS 20 because NSAIDs did not produce substantial improvement in spinal mobility in the validation trials and therefore the group did not consider it a good predictor of response.  The ASAS 20 is modeled, at least in part, on composite outcome measures used in studies of rheumatoid arthritis and osteoarthritis (Anderson et al, 2001). 

Table 31.  Ankylosing Spondylitis Assessment Group Preliminary Definition of Short-Term Improvement in Ankylosing Spondylitis (Anderson et al, 2001)

An improvement of at least 20% and absolute improvement of at least 10 units on a scale of 0‑100 in at least 3 of the following 4 domains:

   Patient global assessment is represented by the VAS global assessment score (0-100 scale)

   Pain is represented by the VAS pain score (0-100 scale)

   Function is represented by BASFI score (0-100 scale)

   Inflammation is represented either by (first choice) the mean of the 2 morning stiffness-related BASDAI VAS scores, or by (second choice) morning stiffness duration with a maximum of 120 minutes (0-100 scale).

Absence of deterioration in the potential remaining domain, where deterioration is defined as a change for the worse of at least 20% and net worsening of at least 10 units on a scale of 0 to 100

VAS = visual analog scale

 

ASAS also defined a low level of disease activity as a “partial remission” of AS represented by a value of < 20 units (scale 1 to 100) in each of 4 domains of the ASAS 20 (Anderson et al, 2001).  This endpoint was intended to provide a clinically meaningful definition of a low disease state independent of change or improvement in the ASAS 20.

3.2                                Disease Controlling Anti-Rheumatic Therapy (DCART)

At a meeting convened October 30 to 31, 2002 to provide input for an FDA Guidance for disease-modifying therapies in AS, an advisory group including many members of the ASAS Working Group developed criteria for disease controlling anti-rheumatic therapy (DCART).  Two composite response criteria were proposed.

The first, here called the DCART 20, combines the 4 criteria of the ASAS 20 with 2 additional criteria:  improvement in spinal mobility and acute phase reactants.  The DCART 20 requires a 20% improvement in 5 of the 6 criteria, with no worsening in the remaining criterion. 

The second, hereafter called the DCART 40, requires a 40% improvement relative to baseline plus absolute improvement of at least 20 units in 3 of the 4 original ASAS 20 criteria, with no worsening in the remaining criterion.  The DCART 40 is an alternative to the DCART 20 that considers different criteria (4 vs 6) and does not indicate a higher level of response than the DCART 20.

4.                                   Description of the Etanercept Development Program for Ankylosing Spondylitis

4.1                                Overview of the Program

The development program for etanercept in AS enrolled and treated 401 subjects with uncontrolled AS despite the use of NSAIDs and other therapies in 3 randomized, placebo-controlled studies.  The first of these was Study 16.0626, a 4-month, proof-of-principle study in 40 subjects that demonstrated encouraging clinical response to etanercept (Gorman et al, 2002).  With proof-of-principle established, 2 studies were initiated:  Study 016.0037 (Amgen; N = 277 subjects), a 6‑month study in the United States, France, Germany, and the Netherlands; and Study 0881A3-311-EU CSR 47687, hereafter referred to as Study 47687 (Wyeth; N = 84 subjects), a 3-month study in 8 European countries.  These studies confirmed the safety and efficacy of etanercept in subjects with AS.  Two open-label studies are ongoing and will allow for up to 2 years of continuous etanercept therapy.

4.2                                Proof of Principle (Study 16.0626)

Study 16.0626 was a double-blind, proof-of-principle study that treated 40 subjects with AS (randomized 1:1) for 4 months with either etanercept (25 mg) or placebo twice weekly (BIW) and offered 6 months of open-label extension therapy.  Inclusion criteria included:  diagnosis of AS by modified New York Clinical Criteria (van der Linden 1984), presence of active disease (morning stiffness ≥ 45 minutes, inflammatory back pain, patient and physician global assessment of moderate or severe disease activity), and stable NSAIDs, steroids (≤ 10 mg of prednisone or equivalent) or DMARDs (methotrexate, sulfasalazine, azathioprine, 6-mercaptopurine).  Subjects were not eligible if other forms of SpA were present, if they had received previous TNF inhibitor therapy, or if they were positive for rheumatoid factor.

Study 16.0626 was designed and conducted before the ASAS 20 was developed.  The investigator prospectively defined response based on 5 clinical domains. The primary efficacy endpoint was the proportion of subjects in each group achieving a 20% improvement (compared with baseline) at week 16 in 3 of 5 response criteria (patient global assessment, nocturnal spinal pain, duration of morning stiffness, Bath Ankylosing Spondylitis Functional Index (BASFI), swollen joint score).  For determination of efficacy, improvement in spinal pain or morning stiffness was required and worsening in the remaining 2 criteria was not permitted.  The study also looked at multiple exploratory secondary endpoints.

The results of this study showed convincing efficacy for etanercept in the composite response criteria and its individual components (Table 41), as well as a reassuring safety profile with an absence of serious adverse events.

Table 41.  Study 16.0626:  Efficacy Results at Week 16

 

 

Placebo

n = 20

Etanercept

n = 20

 

P-value a

Composite Response Criteria: number (%) achieving response

   Responders

5 (25)

15 (75)

0.0038 b

 

 

 

 

Individual components of composite response: mean (median) % improvement

   BASFI

-7.2 (-6.7)

48.7 (47.1)

0.0003

   Nocturnal Back Pain

14.4 (21.5)

61.2 (66.7)

0.0014

   Patient Global Assessment

10.8 (0.0)

28.0 (33.3)

0.0177

   Duration of morning stiffnessc

(18.3)

(76.4)

0.0116

 

n = 11

n = 8

 

   Swollen Joint Score

14.2 (0.0)

46.9 (62.7)

0.2743

a Wilcoxon rank-sum test

b Fisher’s exact test

c Mean % change is not represented as it is highly influenced by a small number of subjects

 

Significant improvement was also seen in some exploratory endpoints including total pain, joint pain/tenderness score, physician global assessment, Dougados Functional Index (DFI), Krupp’s Fatigue Measure, modified Schober’s Test, occiput-to-wall measurement, Westergren ESR, and the physical component summary score (PCS) of the SF-36.

Based on these results, the 2 larger studies were initiated.

4.3                                Pivotal Program

4.3.1                           Study Designs

Studies 016.0037 and 47687 were randomized, double-blind, placebo-controlled, phase 3 trials that randomized subjects in a 1:1 ratio (with stratification by baseline DMARD use) to receive etanercept (25 mg) or placebo BIW.  In Study 016.0037, subjects were followed during 24 weeks of double-blind treatment, and in Study 47687, treatment and observation was for 12 weeks.  Subjects 18 to 70 years old were diagnosed with AS as defined by Modified New York Criteria for Ankylosing Spondylitis.  They had active disease defined by values ³ 30 on a 0 to 100 point VAS for duration/intensity of morning stiffness and 2 of the following 3 parameters:  patient global assessment, average of VAS values for nocturnal back pain and total back pain, or average of 10 questions on the BASFI.  Subjects were not allowed to enroll if they had clinical or radiographic evidence of complete ankylosis of the entire spine; had a history of active or recurrent infection; had ever received etanercept or other TNFa inhibitors; had received any investigational drug therapy within 30 days; had used DMARDs other than hydroxychloroquine, sulfasalazine, or methotrexate within 4 weeks of baseline evaluation; or had changed their dose of NSAIDs or prednisone (£10 mg/ day or equivalent) within 2 weeks of baseline.  Subjects were assessed for safety and efficacy at baseline and weeks 2, 4, 8, and 12 in both studies, and additionally at week 24 in Study 016.0037.

4.3.2                           Study Endpoints

Efficacy

The pivotal program was developed before publication of the ASAS 20 (Anderson et al, 2001) and used an endpoint that differed slightly.  The protocol-defined ASAS 20 used an average of total pain and nocturnal pain scores on the 100-mm visual analog scale (VAS) to represent the pain domain where the published ASAS 20 included only the total pain score. The difference in response criteria had no impact on the significance of the results.

The primary endpoint in both studies was the protocol-defined ASAS 20 criteria for response at week 12. The conditional primary endpoint in Study 016.0037, to be assessed if the primary endpoint was achieved, was the ASAS 20 response at week 24. 

Other endpoints in both studies included frequency and time to partial remission, the individual components of the ASAS 20 (patient global assessment, nocturnal and total back pain, BASFI, and the average of duration and severity of morning stiffness from the Bath AS Disease Activity Index (BASDAI), the assessor global assessment, BASDAI, measurements of spinal mobility (the Schober test, measurement of chest expansion, and occiput-to-wall distance), peripheral joint counts, and laboratory assessment of inflammation (c-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]). 

In addition to the ASAS 20 composite endpoints, the etanercept development program included assessments of higher levels of response based on the ASAS 20.  The ASAS 50 and ASAS 70 are intended to parallel the use of higher levels of standard composite response criteria used in other rheumatic diseases.  They are assessed identically to the ASAS 20 but require 50% and 70% improvement, respectively.

Responses were also assessed in Study 016.0037 with the DCART 20 and DCART 40. Further details on efficacy endpoints are in Appendix 1.

Safety

Safety evaluations in both studies included adverse events evaluated according to Common Toxicity Criteria, premature discontinuation, serious adverse events, deaths on study or within 30 days of last dose of study drug, vital signs and physical exams, hematology profile, chemistry profile, and anti-etanercept antibodies.  See Appendix 1 for further details on safety endpoints.

4.4                                Statistical Analyses

The statistical methods for analyzing efficacy and safety data were the same for Study 016.0037 and Study 47687 unless otherwise noted.  Study 016.0037 and Study 47687 were analyzed using an intent-to-treat approach.  All randomized subjects who received at least 1 dose of study medication were included in the analyses.  All statistical tests were 2-sided and a significance level of 0.05 was used to declare statistical significance between treatment groups.  No adjustments were made for multiple testing.

For binary efficacy endpoints, such as the ASAS 20, 50, and 70, and partial remission, subjects who discontinued from the study were declared nonresponders at all timepoints subsequent to their withdrawal.  The Cochran-Mantel-Haenszel test (as given by the row means test in PROC FREQ from SAS), stratified by presence or absence of concomitant DMARDs at baseline, was used to compare response percentages between treatment groups.  

For continuous efficacy endpoints, such as individual components of the ASAS 20, change and percent change from baseline were compared between the etanercept and placebo groups at each time point using a stratified rank test as obtained in PROC FREQ from SAS using Modridit scores.  Baseline was considered to be the last observation before the first dose of the study.  Change and percent change from baseline were computed for each endpoint such that a value greater than zero reflects improvement unless otherwise noted.  Change and percent change were measured at the subject level and then summarized.  Subjects with a zero score at baseline were not included in the analysis of percent improvement for the variable in question.  A last-observation-carried-forward (LOCF) approach was used to impute missing data.

Safety endpoints:  Treatment groups were compared with respect to incidence of adverse events and infections using Fisher’s exact test for both studies unless otherwise noted.

5.                                   Results for Pivotal Program

5.1                                Study Populations

5.1.1                           Baseline Demographics and Disease Characteristics

The treatment groups were well balanced within studies and were similar across studies with regard to demographic characteristics and baseline DMARDs (Table 5‑1) and baseline disease characteristics (Table 5‑2).

Table 51.  Baseline Demographics and Therapy in the Pivotal Program

 

Study 016.0037

 

Study 47687

 

Baseline characteristic

Placebo

(N = 139)

Etanercept

(N = 138)

 

Placebo

(N = 39)

Etanercept

(N = 45)

Mean age, yrs (range)

41.9
(18 – 65)

42.1
(24 – 70)

 

40.7
(19 – 66)

45.3
(28 63)

Men, n (%)

105 (76)

105 (76)

 

30 (77)

36 (80)

Mean duration of disease (years)

10.5

10.1

 

9.7

15.0

Mean weight (kg)

83.1

82.2

 

73.7

76.1

Race, n (%):

 

 

 

 

 

            White

127 (91)

130 (94)

 

37 (95)

42 (93)

            Other

12 (8)

8 (6)

 

2 (5)

3 (7)

Baseline therapy, n (%):

 

 

 

 

 

            Any DMARD a,b

43 (31)

44 (32)

 

16 (41)

16 (36)

                 Sulfasalazine

30 (22)

29 (21)

 

11 (28)

11 (24)

                 Methotrexate

17 (12)

15 (11)

 

5 (13)

6 (13)

                 Hydroxychloroquine

1 (1)

3 (2)

 

1 (3)

0

            NSAIDs c

128 (92)

126 (91)

 

33 (85)

40 (89)

            Corticosteroids c

20 (14)

18 (13)

 

6 (15)

7 (16)

a  Baseline therapies continued throughout trial.

b Some subjects were taking more than one DMARD.

c Concomitant NSAIDS or corticosteroids taken within 6 months of screening evaluation.

 


Table 52.  Baseline Disease Characteristics in the Pivotal Program

 

Study 016.0037

 

Study 47687

 

Baseline characteristic

Placebo

(N = 139)

Etanercept

(N = 138)

 

Placebo

(N = 39)

Etanercept

(N = 45)

Mean duration of AS, years (range)

10.5 (0 – 35.3)

10.1 (0 – 30.7)

 

9.7 (0.4 – 29.6)

15.0 (0.2 – 37.3)

Extra-spinal disease manifestations, n (%):

 

 

 

 

 

      History of Crohn’s or ulcerative colitis

6 (4)

7 (5)

 

2 (5)

3 (7)

      History of uveitis or iritis

43 (31)

39 (28)

 

6 (15)

13 (29)

      History of psoriasis

15 (11)

11 (8)

 

3 (8)

10 (22)

HLA-B27 positive, n (%)

109 (84)

108 (84)

 

34 (87)

38 (88) a

ASAS 20 b components, mean (range):

 

 

 

 

 

      Patient global assessment

62.9 (9–100)

62.9 (16–100)

 

63.4 (31-86)

65.6 (26-100)

      Total back pain

63.5 (0–99)

61.1 (7–100)

 

56.5 (22-86)

61.9 (22–100)

      BASFI c

56.3 (11.5–97.0)

51.7 (4.3–97.7)

 

57.2 (18.5–82.4)

60.2 (13.9-100)

      Stiffness, duration and intensity

64.3 (7–100)

61.4 (17–100)

 

62.9 (22–99.5)

67.5 (28-100)

Spinal mobility measures, mean (SE):

 

 

 

 

 

      Modified Schober’s scorec, cm

2.97 (0.13)

3.06 (0.15)

 

2.8 (0.22)

2.2 (0.19)

      Chest expansion, cm

3.21 (0.15)

3.26 (0.19)

 

3.9 (0.35)

3.3 (0.27)

      Occiput-to-wall, cm

5.33 (0.56)

5.59 (0.50)

 

4.6 (0.85)

7.3 (0.92)

BASDAIc, mean (SE)

59.6 (1.4)

58.1 (1.5)

 

58.6 (13.2) bd

61.0 (15.7) bd

Acute phase reactants, mean (SE):

 

 

 

 

 

      CRP (mg/dL) ce

2.0 (0.2)

1.9 (0.2)

 

2.4 (4.2) bd

1.9 (1.6) bd

      ESR (mm/hr) df

25.4 (1.9)

25.9 (1.8)

 

33.1 (23.9) bd

30.6 (22.3) bd

a Not assessed for 2 etanercept subjects

b See Appendix 1 for ASAS 20

c See Appendix 1, section 3

d Mean (standard deviation)

c e Normal range 0 to 1.0 mg/dL.

d f Normal range 1 to 17 mm/hr (men), 1 to 25 mm/hr (women)

 


5.1.2                           Study Completion

Completion rates for Study 016.0037 at the 12-week (primary) time point was 96% placebo (134) and 96% etanercept (132).  Completion rates at week 24 in this study were 86% placebo (120) and 91% etanercept (126).  Reasons for premature withdrawal in Study 016.0037 included adverse events (7 etanercept subjects, 1 placebo), lack of efficacy (3 etanercept, 13 placebo), lost to follow-up (2 etanercept, 1 placebo), voluntary withdrawal (2 placebo), and lack of compliance with protocol (2 placebo).  

In Study 47687, 84 subjects were enrolled; 2 subjects in the etanercept group withdrew from study for nonmedical reasons unrelated to safety.

5.2                                Efficacy Results

5.2.1                           Primary Endpoint:  Protocol-Defined ASAS Response

Substantial etanercept-related improvement was evident in the results of the primary endpoint, the protocol-defined ASAS 20, as well as in the protocol-defined ASAS 50, protocol-defined ASAS 70, and partial remission criteria in Study 016.0037 at both the primary (week 12) and conditional primary (week 24) time points (Figure 51).  Almost half the subjects in the study achieved and maintained a protocol-defined ASAS 50, and almost a third achieved a protocol-defined ASAS 70.  Superior response was evident for etanercept-treated subjects at all levels of the protocol-defined ASAS score by week 2 and was maintained throughout the study (p < 0.01 at all visits).  Seventeen percent of etanercept-treated subjects achieved partial remission at week 24 compared with 4% in the placebo group, and etanercept subjects achieved it faster than subjects in the placebo group (log-rank p‑value < 0.0001). 

Results in Table 53 are presented using both the protocol-defined ASAS 20 (see Section 4.3.2) and the ASAS 20 (per Anderson et al, 2001).  Results for both analyses were similar. 

The number of subjects receiving concomitant DMARDs were 44 (etanercept) and 43 (placebo). The responses were similar in etanercept subjects with or without concomitant DMARDs, 61% and 60%, respectively.

Secondary endpoints are presented in Table 54.

The magnitude and time course of etanercept-related improvement was similar in Study 47687 (Table 55), but did not achieve statistical significance for all secondary endpoints, possibly due to the smaller sample size.

Table 53.  Study 016.0037:  Primary Endpoint: 
ASAS 20 at Weeks 12 and 24

 

Protocol-Defined ASAS 20 a

 

ASAS 20 b

 

Parameter

Placebo
N = 139

Etanercept
N = 138

 

P-value c

 

Placebo
N=139

Etanercept
N=138

 

P-value c

ASAS 20 (n/%)

 

 

 

 

 

 

 

12 weeks

38 (27)

83 (60)

< 0.0001

 

39 (28)

82 (59)

<0.0001

24 weeks

32 (23)

80 (58)

< 0.0001

 

31 (22)

78 (57)

<0.0001

a Protocol-defined ASAS 20 is calculated with average of total and nocturnal back pain

b ASAS 20 is calculated using only total back pain (Anderson et al, 2001)

c Cochran-Mantel-Haenszel row means test

 

Table 54.  Study 016.0037:  Secondary Endpoints: 
ASAS 50 and 70, and Partial Remission at Weeks 12 and 24

 

Protocol-Defined ASAS 20 a

 

 

Parameter

Placebo
N = 139

Etanercept
N = 138

 

P-value b

 

ASAS 50 (n/%)

 

 

 

 

12 weeks

18 (13)

62 (45)

< 0.0001

 

24 weeks

14 (10)

58 (42)

< 0.0001

 

ASAS 70 (n/%)

 

 

 

 

12 weeks

10 (7)

40 (29)

< 0.0001

 

24 weeks

7 (5)

39 (28)

< 0.0001

 

Partial Remission (n/%)

 

 

 

 

12 weeks

11 (8)

29 (21)

0.0020

 

24 weeks

5 (4)

24 (17)

0.0002

 

a Protocol-defined ASAS 20 is calculated with average of total and nocturnal back pain

b Cochran-Mantel-Haenszel row means test

 

 

 

Figure 51.  Study 016.0037:  Percent of Subjects Achieving Protocol-Defined ASAS 20, 50, and 70 Over Time

 

Table 55.  Study 47687.  Primary and Secondary Endpoints:
ASAS 20, 50, 70, and Partial Remission at Week 12

 

Parameter

Placebo

N = 39

Etanercept

N = 45

 

P-value a

ASAS 20 (n/%)

9 (23)

27 (60)

0.0008

ASAS 50 (n/%)

4 (10)

22 (49)

0.0002

ASAS 70 (n/%)

4 (10)

11 (24)

0.0973

Partial Remission (n/%)

4 (10)

8 (18)

0.3457

a Cochran-Mantel-Haenszel row means test

 

5.2.2                           Individual Components of ASAS 20

All components of the ASAS 20 reflected substantial etanercept-related improvement at both primary time points (Table 56) and at all other time points measured (p < 0.0005) in Study 016.0037, indicating that etanercept acts on a broad range of disease symptoms.  The median percent improvement in pain was approximately 10-fold higher with etanercept than with placebo, with an apparent advantage in the other component scores.  Comparable efficacy was observed in Study 47687 (Table 57).

Table 56.  Study 016.0037:  Results for Individual Components of Protocol‑Defined ASAS 20

 

 

Mean (median)

Percent Improvement from Baseline  

 

Parameter

Placebo

N = 139

Etanercept

N = 138

 

P-value b

Patient Global Assessment

 

 

 

 

12 weeks

 

9.8 (8.8)

40.2 (50.8)

< 0.0001

24 weeks

 

7.8 (6.5)

38.6 (46.3)

< 0.0001

Avg nocturnal back pain and total back paina

 

 

 

 

12 weeks

 

6.7 (5.4)

39.9 (54.1)

< 0.0001

24 weeks

 

5.1 (6.0)

34.8 (51.1)

< 0.0001

BASFI – average of responses to 10 questions

 

 

 

 

12 weeks

 

4.9 (3.3)

33.1 (32.3)

< 0.0001

24 weeks

 

1.9 (-1.0)

30.1 (31.3)

< 0.0001

Inflammation (BASDAI)

 

 

 

 

12 weeks

 

13.1 (9.5)

44.8 (55.1)

< 0.0001

24 weeks

 

5.7 (5.0)

43.9 (45.0)

< 0.0001

a One subject in the placebo group had a score of zero at baseline for the average nocturnal back pain and total back pain and was not included in the analysis of percent improvement from baseline for that measure

b Cochran-Mantel-Haenszel row means test with Modridit option on percent improvement from baseline

 

Table 57.  Study 47687:  Results for Individual Components of the Protocol‑Defined ASAS 20 at Week 12

 

 

Mean

Percent Improvement from Baseline

 

Parameter

Placebo

N = 39

Etanercept

N = 45

 

P-value a

Patient Global Assessment

 

12.6

37.0

0.0107

Avg nocturnal back pain and total back pain

 

6.2

43.1

0.0003

BASFI – average of responses to 10 questions

 

3.4

35.4

0.0003

Inflammation (Average of last 2 questions on BASDAI related to morning stiffness)

 

15.9

43.3

0.0025

a Cochran-Mantel-Haenszel row means test with Modridit option on percent improvement from baseline.

 

5.2.3                           Additional Measures of Disease Activity

Etanercept therapy was associated with substantial improvement in a number of endpoints not included in the ASAS 20.  Measures of spinal mobility were excluded from the composite criteria because they showed no change in response to NSAID therapy.  Etanercept treatment was associated with significantly more improvement in all 3 measures of spinal mobility than placebo in Study 016.0037 (Table 58), with median percent improvement ranging from 10% to 25% across measures at week 24 compared with 0% in the placebo group. 

Median percent improvement for the indicators of disease activity and inflammation (BASDAI, acute phase reactants) ranged from 40% to 73% in the etanercept group at weeks 12 and 24 and was superior to placebo at every study visit (p < 0.0001).  In the etanercept group, the percent of subjects with normal (nonelevated) acute phase reactants increased from 46% for both reactants at baseline to 83% ESR, 85% CRP at week 24, while in the placebo group they remained unchanged.

Independent assessors judged global disease to be significantly improved in the etanercept group vs placebo at every study visit (p < 0.01), with median percent improvement of 45% at weeks 12 and 24, more than 3-fold higher than with placebo (approximately 13% at both time points).

Tender joint counts improved with etanercept therapy but not swollen joint counts.  The lack of significant treatment effect on swollen joint counts was likely due to the small number of subjects with peripheral joints involved and the small number of joint counts involved in each subject (median swollen joint count at baseline: placebo, 0; etanercept, 1).

Similar improvement was seen in Study 47687 (Table 59 ), although mean percent improvement in joint counts were not available. 

Table 58.  Study 016.0037:  Results for BASDAI, Spinal Mobility, Acute Phase Reactants, Assessor Global, and Peripheral Joint Counts.

 

 

Mean (median)

Percent Improvement from Baseline a

 

Parameter

Placebo

N = 139

Etanercept

N = 138

 

P-value b

BASDAI

 

 

 

 

    12 weeks

 

11.3 (9.9)

42.2 (44.6)

< 0.0001

24 weeks

 

5.8 (3.1)

39.5 (40.4)

< 0.0001

Spinal Mobility Measures

 

 

 

 

Schober’s Test

 

 

 

 

12 weeks

 

21.4 (0)

25.6 (8.6)

0.0359

24 weeks

 

7.8 (0)

25.1 (9.7)

0.0014

Chest Expansion

 

 

 

 

12 weeks

 

11.2 (0)

57.8 (4.8)

0.0026

24 weeks

 

-0.6 (0)

56.5 (16.7)

< 0.0001

Occiput-to-Wall Measurements

 

 

 

 

12 weeks

 

-80.9 (0)

18.3 (15.7)

0.0034

24 weeks

 

-98.7 (0)

26.0 (25.0)

< 0.0001

Acute Phase Reactants

 

 

 

 

ESR (mm/hr)

 

 

 

 

12 weeks

 

-19.2 (0)

17.7 (60.0)

< 0.0001

24 weeks

 

-23.0 (0)

42.1 (60.0)

< 0.0001

C-reactive Protein (mg/dL)

 

 

 

 

12 weeks

 

-142.5 (-5.4)

10.1 (68.5)

< 0.0001

24 weeks

 

-95.9 (0)

38.0 (72.7)

< 0.0001

Assessor Global

 

 

 

 

12 weeks

 

10.3 (13.5)

34.2 (45.0)

< 0.0001

24 weeks

 

5.9 (13.2)

29.5 (45.2)

< 0.0001

 

 

 

 

 

Tender Joint Count

 

n=114

n=101

 

12 weeks

 

-1.0 (20.6)

36.8 (50.0)

0.0061

24 weeks

 

1.4 (31.4)

35.5 (61.5)

0.0014

 

 

 

 

 

Swollen Joint Count

 

n=65

n=73

 

12 weeks

 

-14.6 (50.0)

35.7 (66.7)

0.1263

24 weeks

 

-10.5 (50.0)

3.7 (60.0)

0.8384

a     Subjects with a score of zero at baseline were not included in the analysis of percent improvement from baseline for that measure

b    Cochran-Mantel-Haenszel row means test with Modridit option on percent improvement from baseline.

 

Table 59.  Study 47687:  Results for BASDAI, Spinal Mobility, Acute Phase Reactants, and Assessor Global at Week 12

 

 

Mean

Percent Improvement from Baseline a

 

Parameter

Placebo

N = 39

Etanercept

N = 45

 

P-value b

BASDAI

 

13.6

43.6

0.0014

Spinal Mobility Measures

 

 

 

 

Schober’s Test

 

-1.3

36.0

0.0085

Chest Expansion

 

9.0

29.9

0.8695

Occiput to Wall Measurements

 

7.2

12.5

0.0650

Acute Phase Reactants

 

 

 

 

ESR (mm/hr)

 

0.0

79.6

0.0000

C-reactive Protein (mg/dL)

 

0.0

69.5

0.0000

Assessor Global

 

19.8

39.3

0.0321

a   Subjects with a score of zero at baseline were not included in the analysis of percent improvement from baseline for that measure

b Cochran-Mantel-Haenszel row means test with Modridit option on percent improvement from baseline.

 

5.2.4                           Disease-Controlling Anti-Rheumatic Therapy Response

The DCART 20 and DCART 40 response criteria are discussed in Section 3.2 and are defined in Appendix 1.  

The proportion of subjects who attained the DCART responses was more than 3-fold higher with etanercept therapy than with placebo at week 24 (Table 510).  Statistically significant improvements were evident at all time points during the study compared with the placebo group (data on file).

Table 510.  Study 016.0037: DCART 20 and DCART 40 Responses

 

 

Placebo

N = 139

Etanercept

N = 138

 

P-value*

DCART 20 (n/%)

 

 

12 weeks

11 (8)

51 (37)

< 0.0001

24 weeks

10 (7)

46 (33)

< 0.0001

DCART 40 (n/%)

 

 

12 weeks

21 (15)

59 (43)

< 0.0001

24 weeks

18 (13)

57 (41)

< 0.0001

* P-value determined by Cochran-Mantel-Haenszel row means test.

 

 

5.2.5                           Subgroup Analyses for Study 016.0037

Exploratory analyses were conducted to evaluate the primary endpoint within subgroups defined by baseline demographics (including age, sex, weight, race, HLA-B27, study site, prior use of NSAIDS or corticosteroids, or concomitant DMARD use), baseline disease status (patient global score; average of nocturnal back pain and total back pain; inflammation; BASFI; BASDAI; disease duration; history of extraspinal and extra-articular involvement; hip disease), and occurrence of injection site reactions during the study.  These analyses should be interpreted with caution.  No adjustments for multiple analyses were performed.

The following subgroup variables had significant treatment-by-subgroup interaction p‑values (p<0.05): HLA-B27 status, baseline average of nocturnal back pain and total back pain (above and below median), and baseline BASDAI (above and below median).

In subjects with a positive HLA-B27 test (etanercept, n=108; placebo, n=109), ASAS 20 responses (etanercept, 65%; placebo, 27%) were comparable to the overall study results.  In subjects with a negative HLA-B27 test (etanercept, n=21; placebo, n=20), the week-12 results showed that ASAS 20 was achieved by a similar percentage of subjects in both the etanercept group (38%) and the placebo group (35%).  By week 24, however, a treatment advantage was apparent in ASAS 20 response for etanercept (48% of subjects) vs placebo (20%) among HLA-B27-negative subjects.  The relevance of this finding is unclear, but the relatively small number of HLA-B27-negative subjects may have contributed to this outcome.

For average back pain at week 12, the ASAS 20 responses for the etanercept subgroup compared with the placebo subgroup were 54% vs 34% for subjects with £ median back pain and were 67% vs 22% for subjects with > median back pain.  In both subgroups, the etanercept subjects had significantly higher responses than the placebo subjects.  Similarly, ASAS 20 responses for etanercept compared with placebo were significantly higher in both BASDAI subgroups (56% vs 36% and 65% vs 19% grouped as £ median and > median for BASDAI, respectively).  Neither of the subgroup analyses for back pain or BASDAI suggests a different conclusion regarding the efficacy of etanercept compared with placebo with respect to the primary endpoint.

 

5.3                                Summary of Efficacy Results

Three randomized, double-blind, placebo-controlled clinical trials demonstrated marked efficacy of etanercept in the treatment of AS.  A proof-of-principle trial demonstrated clinical response in its prespecified clinical composite measure as well as in most of the individual response measures used.  Two additional studies, a 277-subject study performed by Amgen (Study 016.0037) and an 84-subject study performed by Wyeth (Study 47687), confirmed the effectiveness of etanercept in treatment of AS.  The primary endpoint in both studies was the proportion of subjects achieving a composite endpoint, the protocol-defined ASAS 20, at 12 weeks.

In study 016.0037, a significantly greater proportion of etanercept-treated subjects (60%) than placebo subjects (27%) met the protocol-defined ASAS 20 at 12 weeks (p < 0.0001).  Since the primary endpoint was significantly greater in the etanercept group, a conditional primary endpoint (protocol-defined ASAS 20 at 24 weeks) was to be evaluated.  The results at 24 weeks were similar to those at 12 weeks with 58% and 23% of subjects achieving the protocol-defined ASAS 20 in the etanercept and placebo groups, respectively.  Additional composite measures were also evaluated: protocol-defined ASAS 50 and ASAS 70, partial remission, DCART 20, and DCART 40.  Each one of these endpoints was achieved by a significantly greater proportion of subjects in the etanercept group compared with the placebo group at all time points measured (weeks 2, 4, 8, 12, and 24). 

The results of the Study 016.0037 are supported by the results of Study 47687.  A significantly greater proportion of etanercept-treated subjects (60%) achieved a protocol-defined ASAS 20 compared with 23% of placebo subjects.  Response rates for higher levels of protocol-defined ASAS 20 were also supportive of Study 016.0037.

Study 47687 supports the conclusions of Study 016.0037 with comparable results.  Etanercept provides clinically and statistically meaningful benefit to subjects with AS.

6.                                   Safety Results

6.1                                Overview of Safety Results

The adverse events profiles seen in Studies 016.0037 and 47687 are summarized in Table 61.  The overall incidence of adverse events was not increased by etanercept in any study, and no deaths were seen.  Etanercept was associated with a higher incidence of injection site reactions.  These findings are further described in the sections that follow.

Table 61.  Overall Summary of Adverse Events in Studies 016.0037 and 47687: Number (%) of Subjects Reporting Adverse Events

 

Study 016.0037

 

Study 47687

 

Placebo
N = 139

Etanercept
N = 138

 

Placebo
N = 39

Etanercept
N = 45

Serious adverse events

5 (3.6)

9 (6.5)

 

0 (0)

1 (2.2)

Medically important infectionsa

1 (0.7)

2 (1.4)

 

0 (0)

0 (0)

Events leading to withdrawal

1 (0.7)

7 (5.1)

 

0 (0)

0 (0)

Non-infectious adverse eventsb

105 (76)

99 (72)

 

23 (59.0)

25 (55.6)

Injection site reactions

13 (9)

41 (30) c

 

6 (15)

15 (33) d

Infections

42 (30)

57 (41)

 

13 (33.3)

16 (35.6)

ISR = injection site reaction 

a Infections requiring hospitalization or parenteral antibiotics

b Excluding infections and injection site reactions

c P < 0.0001, Fisher's exact test

d P = 0.0283, Cochran-Mantel-Haenszel row means test

 

6.2                                Serious Adverse Events

No deaths were reported in any of the studies of etanercept in subjects with AS.  A total of 10 of 183 etanercept-treated subjects (5%) had serious adverse events.

In Study 016.0037, the incidence of serious adverse events was not significantly different in the etanercept (9 subjects) and placebo (5 subjects) groups (Table 62).  The only serious event ocurring in more than a single subject in the etanercept group was bone fracture.  Three subjects sustained bone fracture secondary to trauma.  All cases were considered unrelated to etanercept. 

Table 62.  Study 016.0037:  Summary of Serious Adverse Events

 

Placebo
N = 139

Etanercept
N = 138

Any (n/%)

5 (3.6)

9 (6.5)

 

 

 

Bone fracture (n/%)

0 (0.0)

3 (2.2)

Accidental injury (n/%)

2 (1.4)

0 (0.0)

Cellulitis (n/%)

0 (0.0)

1 (0.7)

Colitis (n/%)

0 (0.0)

1 (0.7)

Fever (n/%)

0 (0.0)

1 (0.7)

Infection (n/%)

0 (0.0)

1 (0.7)

Viral infection (n/%)

1 (0.7)

0 (0.0)

Lymphadenopathy (n/%)

0 (0.0)

1 (0.7)

Intestinal obstruction (n/%)

0 (0.0)

1 (0.7)

Chest pain (n/%)

1 (0.7)

0 (0.0)

Rash (n/%)

0 (0.0)

1 (0.7)

Suicide attempt (n/%)

1 (0.7)

0 (0.0)

In Study 47687, the only serious event was a myocardial infarction in the etanercept group.  The event was considered unrelated to etanercept, therapy was continued, and the subject completed study.

6.3                                Medically Important Infections

Medically important infections were those requiring hospitalization or treatment with intravenous (IV) antibiotics.  Three events occurred in Study 016.0037.  Two occurred in the etanercept group: an infection secondary to a cat bite and cellulitis secondary to an insect bite.  In the placebo group, one subject experienced a viral infection.  No life-threatening infections occurred in Study 016.0037.  No medically important infections occurred in Study 47687.

6.4                      &