Department of Health & Human Services                   Public Health Service

                                                                                                                        Food and Drug Administration

Memorandum                                                                         Center for Biologics Evaluation and Research

                                                                                                                 1401 Rockville Pike

                                                                                                                 Rockville, MD   20852


 

                                                                      Division of Clinical Trial Design and Analysis

                                                                                    HFM-582

 

 

Date:                      May 27, 2003

 

                   

 

 

 

 

 

Advisory Committee Meeting

Clinical Review Briefing Document

 

 

STN  103795 / 5123

 

 

 

Etanercept  for the Treatment of Ankylosing Spondylitis

 

 

 

Applicant:   Immunex, Inc.

 

 

 

 

 

 

 


 

TABLE OF CONTENTS

 

INTRODUCTION--------------------------------------------------------------------------------- 3

 

SUMMARY OF CLINCAL DEVELOPMENT--------------------------------------------- 4

 

SUMMARY OF CLINICAL STUDIES PHASE 2 AND 3-------------------------------- 6

 

STUDY 016.0037

PROTOCOL AND MAJOR AMENDMENTS-----------------------------------------------6

CENTERS, DISPOSITION, DEMOGRAPHY, BASELINE DISEASE,

STUDY CONDUCT-------------------------------------------------------------------------------10

 

STUDY OUTCOMES: PRIMARY EFFICACY--------------------------------------------14

                                        SECONDARY EFFICACY----------------------------------------15

                                        OTHER OUTCOME ANALYSIS--------------------------------18

                                                                                                                                                                                                                                                                                                                                                                                                                                                    EXPLORATORY ANALYSIS------------------------------------------------------------------24

                                        SAFETY----------------------------------------------------------------30

 

CONCLUSIONS-----------------------------------------------------------------------------------35

 

STUDY 47687

PROTOCOL----------------------------------------------------------------------------------------36

CENTERS, DISPOSITION, DEMOGRAPHY, BASELINE DISEASE,

STUDY CONDUCT-------------------------------------------------------------------------------39

 

STUDY OUTCOMES: PRIMARY EFFICACY---------------------------------------------42

                                         SECONDARY EFFICACY----------------------------------------42

                                        OTHER OUTCOME ANALYSIS--------------------------------44

                                        SAFETY----------------------------------------------------------------47

CONCLUSIONS-----------------------------------------------------------------------------------50

 

STUDY 016.0626

PROTOCOL----------------------------------------------------------------------------------------50

 

STUDY OUTCOMES: PRIMARY EFFICACY---------------------------------------------53

                                         AD HOC ANALYSIS-----------------------------------------------54

                                         SECONDARY EFFICACY----------------------------------------55

                                        OTHER OUTCOME ANALYSIS--------------------------------56

                                   

CONCLUSIONS-----------------------------------------------------------------------------------58

 

OVERALL CONCLUSIONS--------------------------------------------------------------------58

 

 

                                       

Introduction

The purpose of this meeting is to present to the Arthritis Advisory Committee data submitted in support of a claim for the use of ENbrel®  (Etanercept) for the treatment of adult patients with Ankylosing Spondylitis (AS) and to discuss issues related to the measurement of clinical efficacy in this disorder.

 

Filing of Application

On January 23, 2003, Immunex Corporation submitted to FDA a License Application for Enbrel®(Etanercept) to extend the Indication to treatment of patients with active Ankylosing Spondylitis

 

Study Products

Etanercept 25 mg administered subcutaneously(SC) twice per week supplied to the pharmacies as a sterile lyophilized powder in vials containing 25 mg of etanercept, 40mg mannitol USP, 10mg sucrose, NF and 1.2 mg TRIS USP

Placebo also administered SC twice per week was supplied in vials identical to above but without the etanercept.

 

Ankylosing Spondylitis and its Treatment

Ankylosing spondylitis is a chronic inflammatory rheumatic disease of unknown etiology associated with HLA-B27.  It affects primarily the sacroiliac joints and the axial skeleton, although peripheral joint involvement may also be an important feature.  Common clinical manifestations include lower back pain and stiffness, chest pain, extra-articular tenderness due to enthesitis (an inflammatory reaction at the site of insertion of tendon into bone) and joint pain and effusion.  Extraskeletal manifestations are seen in some patients, including uveitis, aortic incompetence, cardiac conduction abnormalities and lung fibrosis.  Ankylosing spondylitis belongs to a group of rheumatic disorders, termed spondylarthropathies, that also includes Reiter’s syndrome/reactive arthritis, the arthropathy of inflammatory bowel disease, psoriatic arthritis and undifferentiated spondyloarthropathies.  Symptoms of ankylosing spondylitis are usually manifest by late adolescence or early adulthood.  The course of disease is highly variable.  While it is often self-limited, it may remain active over many years.  Work disability has been observed in up to 15% of patients after 10 years of disease and in up to 45% of patients after 20 years of disease (Guillemin F, Briancon S et al. Arthritis Rheum 33:1001, 1990).  While medications have not been demonstrated to reduce the rate of disability, a number of other interventions have been hypothesized to affect the progression of disability, including physiotherapy, vocational counseling and job training.

 

Approximately 350,000 patients in the United States have been diagnosed with AS. A variety of non-steroidal anti-inflammatory drugs (NSAIDS) are approved for treatment of signs and symptoms of AS. Certain drugs which are considered disease-modifying drugs (DMARDS) in rheumatoid arthritis (RA) such as Sulfasalazine or Methotrexate are used by some clinicians in AS but none are FDA approved for this use There are no data from randomized controlled clinical trials to support clinical benefit for DMARDS in AS.

 

Tumor necrosis factor (TNF) levels have been shown to be elevated in serum and synovial tissue of patients with AS. These findings provide a rationale for the study of the TNF blocking agent etanercept to reduce the clinical signs and symptoms of AS.

 

Etanercept has been approved for the treatment of Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis and Psoriatic Arthritis based upon randomized controlled trials that have shown safety and efficacy. Since AS may share pathogenic mechanisms with these disorders, efficacy for etanercept in these other disorders supports the rationale to study etanercept in AS.

 

Development of Efficacy Endpoints for Clinical Trials

Derivation of the ASAS Response Criteria

One of the difficulties encountered by investigators seeking to demonstrate benefit of various therapeutic modalities has been the lack of a outcome assessment similar to the ACR 20 used in Rheumatoid Arthritis to assess short-term benefit of therapies in this chronic disease. Over the years a number of questionnaire based instruments have been developed including the Bath Ankylosing Spondylitis Functional Index (BASFI) which measures the physical function impairment caused by AS, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) which focuses upon signs and symptoms of the inflammatory aspects of AS, nocturnal and total back pain, the patient’s global assessment and actual physical measurements of spinal mobility such as the Schober’s test, chest expansion score and Occiput to wall measurement. The Assessments in Ankylosing Spondylitis (ASAS) Working Group developed and published a core set of 5 domains whose evaluation were deemed essential in the evaluation of the therapeutic efficacy. These domains were: physical function, pain, spinal mobility, spinal stiffness/inflammation and patient’s global assessment. In 2001, the ASAS Working Group published the ASAS Response Criteria based upon analysis of 5 randomized trials of NSAIDS in AS which enrolled 1030 patients for £ 6 weeks of treatment. Four of the  five  necessary domains were included in the Response Criteria since in these placebo response rates were low and using these response criteria effectively differentiated drug effect from placebo. The remaining domain, spinal mobility was omitted from the Response Criteria because of a lack of responsiveness possibly owing to the lack of effect of NSAIDS on spinal mobility as well as the short duration of treatment.

 

The ASAS Working Group Response Criteria were used in both Phase 3 studies in this application, and were compared with pre-specified response criteria used in the phase 2 study.

 

Clinical Studies of Etanercept for Ankylosing Spondylitis

The studies of etanercept in AS are summarized in (Table 1)

Table 1 Clinical Studies of Etanercept 25mg biw for Ankylosing Spondylitis

Protocol No. Study Objectives

Treatment Duration           N

Treatment Groups 

                      

016.0026 Phase 2

Efficacy and safety

16 weeks                              20

Etanercept 25mg sc biw

16 weeks                              20  

Placebo sc biw

016.0037 Phase 3

Efficacy, safety, PK

24 weeks                             138

Etanercept 25mg sc biw

24 weeks                             139

Placebo sc biw

47687 Phase 3

Efficacy and safety

12 weeks                              45

Etanercept 25mg sc biw

12 weeks                              39

Placebo sc biw

 

Including patients participating in the phase 2 study and the two phase 3 studies to be discussed, a total of 203 patients with active Ankylosing Spondylitis have received etanercept at 25mg sc biw for a duration of between 12 and 24 weeks during the conduct of this clinical development (Table 1).

 

Etanercept (Enbrel) is a dimeric fusion protein consisting of the human p75 tumor necrosis factor (TNF) receptor linked to the Fc portion of human IgG1.  It binds specifically to TNF and blocks its interaction with cell surface TNF receptors.  It is approved for treatment of moderately to severely active rheumatoid arthritis and for treatment of active arthritis in patients with psoriatic arthritis.  Etanercept is approved as monotherapy or in combination with methotrexate for patients who do not respond adequately to methotrexate alone.  It has been shown to reduce signs and symptoms in rheumatoid arthritis and to inhibit the progression of structural damage.  It is also approved for treatment of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients who have had an inadequate response to one or more DMARDs.  

 

The safety of etanercept has been studied in clinical trials of approximately 1200 patients with RA, followed for up to 36 months and in 157 patients with psoriatic arthritis for 6 months.  In addition, over 100,000 patients have been exposed to the marketed product.  Serious adverse events are observed infrequently with etanercept and include serious infections and sepsis, demyelinating syndromes and lupus-like syndrome.  A recent FDA analysis of the clinical trial data with etanercept, infliximab and adalimumab suggested that use of TNF-blocking agents may be associated with a higher risk of  lymphoma.  For etanercept, the rate of lymphoma was 2-fold higher than that expected in the general population.  However, patients with rheumatoid arthritis, particularly those with highly active disease, may be at a higher risk for the development of lymphoma.

 

 

 

 

 

Summary of Phase 2 Study

The phase 2 Study 160026 was a randomized, double-blind, placebo controlled trial designed to explore the clinical efficacy of etanercept in controlling disease activity of AS in conjunction with the use of standard medication for AS. Eligible patients were randomized 1:1 to receive either etanercept 25 mg biw or placebo biw. Duration of the trial was 16 weeks with 4 weeks of safety follow-up. This trial commenced in 1999 prior to the publishing of the ASAS Working Group Response Criteria and utilizes a somewhat different set of Clinical Response Criteria that comprised the Bath Ankylosing Spondylitis Functional Index (BASFI), Nocturnal back pain Visual Analogue Scale (VAS), Patient Global Assessment VAS, Duration of Morning Stiffness and Swollen Joint Score. analysis using the pre-specified endpoint indicated increased response rate associated with etanercept treatment.  In addition, an ad hoc analysis using the ASAS Working Group Response Criteria was performed and it also showed increase in response incidence with etanercept treatment.   This study will be reviewed further later in this document

 

Rationale for Selection of Etanercept Dosage for Phase 3

Etanercept at a dose of 25 mg administered SC twice weekly was selected for this study

based on clinical trials in patients with RA and psoriatic arthritis, which have

shown this to be an effective dose, and because this dose appeared to provide benefit in

the earlier Phase 2 trial in patients with AS ~xr241i ~xr242i

 

Summary of Study 016.0037

Study Title

“ Multicenter, double-blind, Placebo-controlled, Randomized Phase 3 Study of Etanercept (ENBREL®) in the Treatment of Patients with Ankylosing Spondylitis”

 

Study Design

Study 016.0037 was a randomized, multicenter, international, double blinded, placebo-controlled phase 3 study of etanercept versus placebo in 277 patients with active ankylosing spondylitis. Subjects were randomly assigned to one of two treatment arms: etanercept 25mg sc biw or placebo on a 1:1 basis. Subjects were treated for a total of 24 weeks with the primary efficacy endpoint determined at week 12 and a conditional primary efficacy endpoint determined at week 24 if efficacy was demonstrated at week 12. There were 4 weeks of safety follow-up after the 24 weeks of study treatment. Randomization was stratified for the presence of DMARDS approved for use in the study. These were Sulfasalazine, Methotrexate and Hydroxychloroquine.

 

Dosing and Dosing Modification

Etanercept 25 mg or placebo was administered sc twice per week for 24 weeks in patients with active AS who met eligibility criteria. There was no provision for dose modification of study drug. Patients who developed a Grade 3 or 4 adverse event thought to be related to study treatment could suspend study drug for one week but if 4 consecutive doses of study drug were missed, the subject was withdrawn from the study. In this situation, the subject was considered to be a treatment non-responder for efficacy and would continue for an additional 30 days for safety analysis.

Study Population

Men and women, outpatients, between 18 and 70 years of age with AS, as defined by the modified New York Criteria for Ankylosing Spondylitis (Table 60 Appendix A) which was active at the time of enrollment as defined by:

- visual analog scale (VAS) values ³ 30 (on a scale of 0–100) for the following parameter:

- Average of duration and intensity of morning stiffness

PLUS VAS values ³ 30 for 2 of the following 3 parameters:

- patient global assessment

- average of VAS values for nocturnal back pain and total back pain

- average of 10 questions on the BASFI. 

 

Excluded were subjects with:

Complete Ankylosis of the spine

use of DMARDS other than Sulfasalazine, Methotrexate, or Hydroxychloroquine

Previous Receipt of Etanercept or other TNFa-blocking agents

Dose of prednisone > 10mg/d or changed within 2 weeks of   baseline evaluation

Dose of NSAIDS changed within 2 weeks of baseline

 

Primary Efficacy Outcome

The primary efficacy outcome was determined at 12 weeks of treatment using the following ASAS Response Criteria

  • Primary Efficacy Endpoints:

ASAS Response Criteria (ASAS 20) at 12 weeks defined as follows:

    • An improvement of at least 20% and absolute improvement of at least 10 units on a 0-100mm scale in at least 3 of the following domains:
      • Patient global assessment measured on a VAS scale with extremes labeled “none” and “severe.” (Table 65 Appendix F)
      • Pain assessment represented by the average of total and nocturnal pain scores, both measured on a VAS scale with extremes labeled “no pain” and “most severe pain.” (Table 66 Appendix G)

·       Function represented by BASFI average of 10 questions regarding ability to perform specific tasks as measured by VAS with extremes labeled “easy” and “impossible.” (Table 62 Appendix C)

      • Inflammation, represented by the average of the last 2 questions on the 6- question BASDAI regarding morning stiffness as measured by VAS: one (No. 5) with extremes labeled “none” and “very severe”; the other (No. 6) marking duration of morning stiffness between “0” and “2 or more hours.” (Table 63 Appendix D)
    • Absence of deterioration (of at least 20% and absolute change of at least 10 units on a 0–100 mm scale) in the remaining domain.

 

Secondary Efficacy Outcomes:

Secondary Efficacy Outcomes included:

·       the ASAS Response Criteria of 50% and 70% improvement at weeks 12 and 24 which were calculated as follows:

- The ASAS 50 response was to be computed and analyzed using rules similar to those defined for the ASAS 20 response criteria, except that a 50% improvement was required for 3 of the 4 components, in addition to a ³ 10 point absolute improvement in the change scores for 3 of the 4 components. The deterioration criteria were to be defined exactly as for the ASAS 20 response criteria (worsening of 20% or more and absolute worsening of ³10 points).

- The ASAS 70 response was to be computed and analyzed using rules similar to those defined for the ASAS 50 response criteria, except that a 70% improvement was required.

-Additional analysis of ASAS response at Weeks 12 and 24:

  • Highest ASAS Level Achieved

- Patients were to be classified on 1–4 scale according to their highest response status with respect to ASAS 20, ASAS 50, and ASAS 70 endpoints.

            - 1 = non-responder (did not achieve ASAS 20 response)

- 2 = ASAS 20 responder, but not ASAS 50 responder

- 3 = ASAS 50 responder, but not ASAS 70 responder

- 4 = ASAS 70 responder

  • Partial Remission

Frequency and time to the ASAS definition of partial remission defined as:

7i       Value of < 20 (on a scale of 0–100) in each of the following 4 domains

- Patient global assessment as determined by VAS.

- Pain score (average of total back pain/nocturnal back pain) determined by VAS.

- BASFI.

- Average of responses to 2 questions regarding morning stiffness on the 6-question Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

 

Additional Outcome Measures:

In addition to the primary and secondary endpoint analysis as listed above, additional outcome analysis was performed using both the individual components of the ASAS Response Criteria as well as Components of Other AS Instruments.

 

Individual components of the ASAS Instrument

  • Patient global assessment
  • Nocturnal back pain, total back pain, and the average of the nocturnal back pain and total back pain scores
  • The BASFI and its independent components
  • The BASDAI and its independent components

 

Components of Other AS Instruments

  •  Spinal mobility (change and percent change from baseline) assessed by:
    • modified Schober’s test
    • chest expansion score
    • occiput-to-wall measurement.
  • Peripheral tender joints and swollen joint count (change and percent change from baseline).
  • Laboratory assessment of inflammation (CRP and ESR), change and percent change from baseline.
  • Patient-reported improvement in AS at 2 weeks (percent of patients).
  • Assessor global assessment (change and percent change from baseline).

 

 

 

 

Withdrawal for Lack of Efficacy

patients could be discontinued from study treatment for lack of efficacy defined as failure to improve 3 of 4 ASAS Response Criteria by 10% or more at week 8 (and 12) and at early termination visit. Such an individual would be considered an efficacy non-responder and would continue for 30 days for safety analysis only.

 

Clinical and Laboratory Evaluations

Patients were assessed for both efficacy and safety at weeks 2,4,8,12, 24 (or Early Termination) and at 30-day follow-up. All components of the ASAS Response Criteria as well as Assessor global score and blinded joint assessment were performed at these times.  Physical examination including vital signs as well as measurements of spinal mobility were performed at those visits. Laboratory evaluation including Chemistry profile, urinalysis were scheduled to be performed at baseline, week 12 and 24 and at 30 day follow-up. ESR and C-reactive Protein were to be performed with each efficacy/safety visit except for the 30 day follow-up. All Laboratory tests except ESR were performed  centrally and all results were withheld from the investigator until after the study was un-blinded.

Statistical Analyses

Primary efficacy analysis

  • The primary efficacy population was the modified Intention to Treat population which was defined as all subjects randomized and who received at least one dose of study medication. The acceptance of the modified Intention to Treat population was contingent upon the number of randomized but not treated being small and balanced between the two arms. Otherwise, the primary analysis population would be the strict intend to treat population, i.e. all randomized patients.
  • The ASAS 20 response rates were to be compared between the etanercept and placebo groups at each time point using the Cochran-Mantel-Haenszel test stratified by presence or absence of concomitant DMARDS at baseline.  

 

Secondary analyses:

  • For binary endpoints (ASAS 50 and ASAS 70 response rates, partial remission of AS, and patient improvement at 2 weeks), the Cochran-Mantel-Haenszel row means test, stratified by presence or absence of concomitant DMARDs at baseline, was to be used to compare the etanercept and placebo treatment groups at each time point.
  • For patient and assessor global assessment, back pain, BASFI, BASDAI, chest expansion score, modified Schober’s test, occiput-to-wall measurement, numbers of tender and swollen joints, and acute phase reactants, change and percent change from baseline were to be 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. The p-value obtained from the row-means test statistic was to be used. Change and percent change from baseline were computed for each variable such that a value greater than zero reflects improvement. Values were measured at the patient level and then summarized. Patients with a score of zero at baseline were not included in the analysis of percent change for the variable in question. The scores for the highest response status (scale of 1– 4) with respect to ASAS 20%, 50%, and 70% responses were to be compared between the etanercept and placebo groups at each time point using the exact Kolmogorov-Smirnov test as given by PROC NPAR1WAY in SAS based on 500,000 Monte Carlo simulations. The time to first partial remission was to be analyzed using the log-rank test to compare between the etanercept and placebo groups.

All tests were 2-sided, conducted at the a = 0.05 level.

Patients who prematurely discontinued from study drug were considered non-responders for all binary endpoints at time points after study drug discontinuation.

Major Protocol Amendments

Amendment 1: submitted approximately 6 weeks after the original protocol was approved this protocol increased the number of participating centers to 30 from 25 to insure rapid accrual, provided for a conditional primary endpoint defined by ASAS Response Criteria at Week 24 to be assessed if efficacy is established at Week 12, established that inclusion criteria were to be applied prior to randomization rather than enrollment, provided for Lack of Efficacy withdrawal at weeks 8, 12 and early termination visit rather than just after 12 weeks of treatment.

There were no additional protocol amendments

 

Study Results

 

Study Centers

There were 28 participating study centers in US, Europe, and Canada. The majority of the subjects participated at North American Sites (78%)

 

Patient Disposition

330 patients were screened, 284 were randomized and 277 were randomized and received at least one dose of the study medication. Of the 46 individuals screened but not randomized, 40 were found to be ineligible, the remainder declined participation.  Of the 7 individuals who were randomized but did not receive study medication, 4 had been randomized in error (did not meet inclusion criteria) and 3 withdrew consent prior to first dose. These 7 individuals were equally balanced across both study arms . Of the 277 individuals that were randomized and received study medication, 138 received etanercept and 139 received placebo. 96% of all participants completed 12 weeks of study, and 86% of placebo and 91% of etanercept recipients completed 24 weeks of participation. Adverse Events were the most common reason for withdrawal in the etanercept group (7 patients or 5%) and Lack of Efficacy most common reason in the placebo group (13 patients or 9%) (Table 2)

 

 

 

 

 

Table 2: Study Completion Status at 12 and 24 Weeks

 

Placebo

Etanercept

 

(N = 139)

(N = 138)

Patient Status

n (%)

n (%)

Randomized but not dosed

3/142 (2)

4/142 (3)

Completed 12 weeks in study

134 (96)

132 (96)

Discontinued study (wks 0-12) due to:

 

 

Adverse event

0

4 (3)

Lack of efficacy (LOE)

2 (1)

1 (1)

Lost to follow-up

0

1 (1)

Patient refusal

2 (1)

0

Physician decision

1 (1)

0

Completed 24 weeks in study

120 (86)

126 (91)

Discontinued study (wks 0-24) due to:

 

 

Adverse event

1 (1)

7 (5)

Lack of efficacy (LOE)

13 (9)

3 (2)

Lost to follow-up

1 (1)

2 (1)

Patient refusal

2 (1)

0

Physician decision

2 (1)

0

 

Patient Demographics

The mean age of study participants was approximately 42 years of age in both study arms. The study excluded pediatric patients and there was an upper age limit of 70 years of age. The mean weight of participants was approximately 82 kg in both arms with the recorded range from 47 kg and 165 kg. Etanercept was administered as fixed doses.

 

76% of the participants were male which reflects the higher prevalence of AS in men. More than 91% of participants were Caucasian, minority participation was low in both arms with only one subject identified as black in either arm (Table 3).

 

 

 

 

Table 3 Demographics 016.0037

 

Placebo

Etanercept

Characteristic

N = 139

N = 138

Mean age in years

41.9

42.1

Male (n [%])

105 (76)

105 (76)

Race (n [%]):

 

 

Caucasian

127 (91)

130 (94)

Hispanic

6 (4)

3 (2)

Asian

3 (2)

3 (2)

Native American

3 (2)

0

Black

0

1 (1)

Other

0

1 (1)

Mean weight (kg)

83.1

82.2

 

Disease Characteristics at Baseline

Axial Disease Characteristics

The mean duration of ankylosing spondylitis was similar in both arms at approximately 10 years. The percentage of HLA B-27 antigen positivity was identical at 84% in both arms and reflects the prevalence in the general patient population. Baseline assessment using the ASAS components indicated that the subjects had moderate mean values of disease activity and were well balanced between study arms. Approximately 92% of subjects had a history of NSAIDS usage, 13% had history of prior corticosteroid usage and 41% had received prior DMARDS. Approximately 32% of individuals in both arms were on protocol permissible DMARDS at baseline; the most common DMARD in both arms was Sulfasalazine (Table 4). Approximately 14% of placebo recipients and 12% of etanercept recipients received corticosteroids during the study, the most common reason for corticosteroid use was flare of pre-existent ocular inflammatory conditions.

Table 4 Baseline Disease Characteristics

 

Placebo

Etanercept

Characteristic

N = 139

N = 138

Mean duration of AS in years

11

10

HLA B-27

109(84)

108(84)

Mean baseline ASAS components (range):

 

 

Patient global assessment

63(9–100)

63(16–100)

Nocturnal and total back pain

62 (0–99)

60 (6–100)

BASFI

56 (12–97.0)

52 (4–98)

Inflammation

64 (7–100)

61. (17–100)

Concomitant therapy at baseline (n [%]

 

 

Any DMARD

43 (31)

44 (32)

Sulfasalazine (SSZ)

30 (22)

29 (21)

Methotrexate (MTX)

17 (12)

15 (11)

Hydroxychloroquine (HCL)

1 (1)

3 (2)

 

Extra-Spinal Inflammatory Signs/Symptoms

Overall approximately 30% of participants had a history of or concurrent manifestations of extra-spinal inflammatory signs and symptoms. occular inflammation or uveitis/iritis were the most common extra-spinal inflammatory conditions at approximately 30% in both arms. Patients with history of inflammatory bowel disease and psoriasis were included in the study and made up approximately 5% and 9% of the study population respectively (Table 5). These factors were well balanced between the two study arms.

Table 5 Extra-Spinal Inflammatory Symptoms

Extra-Spinal/Articular Inflammatory Symptom

Placebo

n/N  %

Etanercept

n/N %

Occular Inflammation

39/139 (28)

44/138 (32)

Non-Infectious Conjunctivitis

11/139  (8)

9/138 (7)

Uveitis or Iritis

43/139 (31)

39/138 (28)

Crohns Disease or Ulcerative Colitis

6/139  (4)

7/138 (5)

Urethritis

8/139  (6)

5/138 (4)

STD

13/139 (9)

11/138 (8)

Psoriasis

15/139 (11)

11/138 (8)

 

Primary Efficacy Analysis

The primary efficacy endpoint in this study was the achievement of an ASAS 20 using the ASAS Working Group Response Criteria. 60% of Etanercept recipients versus 27% of placebo recipients achieved the primary endpoint which was statistically significant with a p-value of <0.0001 (Table 6).

Table 6 Primary Endpoint Study 016.0037

Primary Endpoint

Number (%) Achieving ASAS 20 Response at Week 12

 

Placebo

Etanercept

 

Parameter

N = 139

N = 138

P-value*

ASAS 20 at 12 weeks

38 (27)

83 (60)

< 0.0001

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

 

Because the primary endpoint at 12 weeks was achieved, the ASAS Response Criteria data at 24 weeks was assessed as a conditional primary endpoint. In this analysis, ASAS 20 levels were achieved by 58% of Etanercept recipients versus 23% of Placebo recipients (p-value of  <0.0001) (Table 7).

 

Table 7 Conditional Primary Endpoint Study 016.0037

Conditional Primary Endpoint:

Number (%) Achieving ASAS 20 at Week 24

 

Placebo

Etanercept

 

Parameter

N = 139

N = 138

P-value*

ASAS 20 at 24 weeks

32 (23)

80 (58)

< 0.0001

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

 

Secondary Efficacy Analysis

There were 8 Secondary Efficacy Endpoints: Measurement of ASAS 50/70 at 12 and 24 weeks, Highest ASAS level achieved at 12 and 24 weeks and Frequency and time to Partial Remission as previously defined

ASAS 50/70 at 12 and 24 weeks

Higher levels of response using the ASAS Response Criteria were analyzed. The superior performance of etanercept compared to placebo was also seen in the ASAS 50 and 70 determinations with significant p-values at both 12 and 24 weeks (Table 8).

 

Table 8 Secondary Endpoints ASAS 20, 50, 70:  12/24 weeks

Secondary Endpoints:

 

 

Placebo

Etanercept

 

Parameter

N = 139

N = 138

P-value*

ASAS 20 (n [%]) at:

 

 

 

12 weeks

38 (27)

83 (60)

< 0.0001

24 weeks

32 (23)

80 (58)

< 0.0001

ASAS 50 (n [%]) at:

 

 

 

12 weeks

18 (13)

62 (45)

< 0.0001

24 weeks

14 (10)

58 (42)

< 0.0001

ASAS 70 (n [%]) at:

 

 

 

12 weeks

10 (7)

40 (29)

< 0.0001

24 weeks

7 (5)

39 (28)

< 0.0001

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

 

 

The onset of etanercept treatment effect compared to placebo began to be apparent as early as 2 weeks after treatment initiation. Maximal treatment effect was reached at approximately 8 weeks and sustained thereafter (see Figure 1). The time courses of effect with respect to ASAS 20, 50, and 70 values were similar although smaller proportions of patients attained the higher levels of response criteria (Figure 1)

 

Figure 1: Percent of Patients Achieving ASAS 20, ASAS 50, and ASAS 70 Over Time


Highest ASAS Responses at weeks 12/24

analysis of highest ASAS response achieved indicate that among the patients whose highest response was ASAS 20 ( did not achieve an ASAS 50 or ASAS 70 response), the numbers and percentages are similar between the two study arms at the 12 and 24 week time points Higher proportions of etanercept treated patients achieved higher level (ASAS 50, 70) responses (Table 9).

  Table 9 Secondary Endpoint Study: Highest ASAS Responses Achieved at weeks 12/24

 

Secondary Endpoint: Highest ASAS 12/24 weeks

 

 

 

Placebo

Etanercept

 

Time point

Highest level of response

N = 139

N = 138

P-value*

Week 12

ASAS 20 non-responder

101 (73)

55 (40)

< 0.0001

 

ASAS 20 responder

20 (14)

21 (15)

 

 

ASAS 50 responder

8 (6)

22 (16)

 

 

ASAS 70 responder

10 (7)

40 (29)

 

Week 24

ASAS 20 non-responder

107 (77)

58 (42)

< 0.0001

 

ASAS 20 responder

18 (13)

22 (16)

 

 

ASAS 50 responder

7 (5)

19 (14)

 

 

ASAS 70 responder

7 (5)

39 (28)

 

* P-value determined by Kolmogorov-Smirnov test.

 

Partial Remission

As previously indicated, partial remission was defined as achievement of a disease activity level <20 on VAS in all 4 ASAS domains. Etanercept patients achieved partial remission statistically more often than placebo both at the weeks 12/24 endpoints as well as any time during the study (Table 10).

Table 10 Secondary Endpoint Study Achievement of Partial Remission

Secondary Endpoint: Partial Remission

 

 

Placebo

Etanercept

 

 

N = 139

N = 138

 

Time point

n (%)

n (%)

P-value*

Week 12

11 (8)

29 (21)

0.0020

Week 24

5 (4)

24 (17)

0.0002

Any time during the study

15 (11)

42 (30)

< 0.0001

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

 

 

The time to achievement of first partial remission was also analyzed and etanercept was statistically superior to placebo (log-rank p-value <0.0001) as shown graphically in (Figure 2).

 

 

Figure 2 Time to First Partial Remission

Other Efficacy Analysis

Individual Components of ASAS Response Criteria

Response data corresponding to each of the components of the 4 domains that comprise the ASAS Response Criteria were individually analyzed. The components analyzed using a Visual Analog Scale were: patient global assessment, average of nocturnal back pain and total back pain, the average of the 10 questions of the BASFI (function) and the last two questions of the BASDAI (inflammation). The results of this analysis indicated that subjects receiving etanercept  had statistically greater improvement in each of the ASAS components than did subjects receiving placebo (Table 11).

 

 

 

 

 

 

 

 

 

 

 

 

Table 11 ASAS Individual Components

ASAS Individual Components

Mean (median) Values and Percent Improvement from Baseline

 

 

Mean(median)

 

Mean (median) Values
Percent Improvement from Baseline

 

Placebo

Etanercept

Placebo

Etanercept

P-value
Parameter

N = 139

N = 138

N = 139

N = 138

 

Patient’s Global Assessment

Placebo

Etanercept

Placebo

Etanercept

 

Baseline

63 (64)

63 (66)

 

 

 

12 weeks

56 (57)

35 (32)

10 (9)

40.2 (51)

< 0.0001

24 weeks

56 (57)

36 (29)

8 (7)

38.6 (46)

< 0.0001

Average of Nocturnal Back Pain/ Total Back Pain

Placebo

Etanercept

Placebo

Etanercept

P-value

Baseline

62 (65)

60 (62)

 

 

 

12 weeks

55 (56)

33 (26)

7 (5)

40 (54)

< 0.0001

24 weeks

56 (61)

34 (26)

5 (6)

35 (51)

< 0.0001

BASFI

Placebo

Etanercept

Placebo

Etanercept

P-value

Baseline

56 (59)

52 (50)

 

 

 

12 weeks

53 (53)

35 (29)

5 (3)

33 (32)

< 0.0001

24 weeks

55 (55)

36 (31)

2 (1)

30 (31)

< 0.0001

BASDAI (last 2 questions)

Placebo

Etanercept

Placebo

Etanercept

P-value

Baseline

64 (65)

61.4 (60)

 

 

 

12 weeks

53 (49)

32.8 (21)

13 (10)

45 (55)

< 0.0001

24 weeks

57 (58)

33.4 (26)

6 (5)

44 (45)

< 0.0001

 

Additional Outcome Measurements

Efficacy measurements not part of the ASAS Response Criteria but which had been used in other studies of Ankylosing Spondylitis were also analyzed. These outcome measurements included: BASDAI (all 6 questions), spinal mobility parameters, peripheral tender and swollen joints, acute phase reactants and assessor global assessment.

BASDAI

The last 2 questions of the BASDAI deal with inflammation and are assessed in the ASAS response criteria. The other 4 questions address fatigue; AS related neck, back or hip pain; non-AS pain and swelling of joints and tenderness to touch of any areas. These data were collected and the results are presented in (Table 12). Again, the improvement in the etanercept group is statistically superior to the placebo.

 

 

Table 12 BASDAI Average of 6 questions

 

 

 

Mean (median)

 

Mean (median) Values

Percent Improvement from Baseline

BASDAI – average of

Placebo

Etanercept

Placebo

Etanercept

 

responses to 6 questions

N = 139

N = 138

N = 139

N = 138

P-value*

Baseline

60 (60)

58 (57)

 

 

 

12 weeks

52 (50)

33(27)

11 (10)

42 (45)

< 0.0001

24 weeks

55 (58)

35 (33)

6 (3)

40 (40)

< 0.0001

* P-value determined by Cochran-Mantel-Haenszel row means test with Modridit option on percent

improvement from baseline.

Spinal Mobility Parameters

Spinal mobility was judged by the ASAS Working Group as the fifth important domain in the assessment of clinically important short-term therapeutic response in Ankylosing Spondylitis but this domain was not included in the ASAS Response Criteria (see Development of Efficacy Endpoints for Clinical Trials pg 3). Assessment of Spinal Mobility was separately performed in this study and these data are presented in (Table 13). Statistically significant improvements in spinal mobility in all three measured parameters were demonstrated by etanercept. The parameter demonstrating the greatest improvement was Occiput to wall measurement.

Table 13 Other Endpoints: Spinal Mobility Parameters

Spinal Mobility Parameters:

Mean (median) Values and Percent Improvement from Baseline

 

 

Mean (median)

 

Mean (median) Values (cm)

Percent Improvement from Baseline*

 

Placebo

Etanercept

Placebo

Etanercept

 

Parameter

N = 139

N = 138

N = 139

N = 138

P-value

Modified Schober’s test

 

 

 

 

 

Baseline

3.0 (3)

3.1 (3)

 

 

 

12 weeks

3.1 (3)

3.3 (3)

21 (0)

26 (9)

0.0359

24 weeks

2.9 (3)

3.3 (4)

8 (0)

25 (10)

0.0014

Chest expansion

 

 

 

 

 

Baseline

3.2 (3)

3.3 (3)

 

 

 

12 weeks

3.2 (3)

3.8 (3)

11 (0)

58 (5)

0.0026

24 weeks

3.0 (3)

3.9(4)

-<1 (0)

57 (17)

< 0.0001

Occiput-to-wall Measurement

 

 

 

 

 

Baseline

5.3 (3)

5.6 (5)

 

 

 

12 weeks

5.7 (3)

4.9 (3)

-18 (0)

18 (16)

0.0034

24 weeks

6.0 (3)

4.5(1)

-18 (0)

26 (25)

< 0.0001

* Patients with a score of zero at baseline were not included in the analysis of percent improvement from baseline.

The number of patients with a zero baseline score varied, depending on the parameter of interest.

† P-value determined by Cochran-Mantel-Haenszel row means test with Modridit option on percent

improvement from baseline.

 

 

 

 

 

Peripheral Tender and Swollen Joint Counts

Improvement in peripheral joint symptoms have been analyzed in other studies of Ankylosing Spondylitis and were assessed here. Treatment with etanercept was associated with statistically significant improvement in numbers of tender peripheral joints (Table 14). There was, however, no corresponding statistically significant improvement in the numbers of swollen joints (Table 14).  The explanation for this finding is not established but is possibly related to the small number of involved joints symptoms in subjects in both study arms or to the lack of etanercept efficacy. At baseline, 82% of placebo recipients and 73% of etanercept recipients had at least one tender peripheral joint, 47% and 53% of these same groups had evidence of swelling in at least one peripheral joint. For those individuals who did have tender joints at baseline, the mean number was 9 in placebo and 7 in etanercept arms, with corresponding medians of 4 and 3 respectively. The mean number of swollen joints was 4 in both arms with corresponding medians of 0 for placebo and 1 for  etanercept.

Table 14 Other Endpoints: Peripheral Tender and Swollen Joint Counts

Peripheral Tender and Swollen Joint Counts

Mean (median) Values and Percent Improvement from Baseline

 

 

Mean (median)

 

 

Mean (median) Values

Percent Improvement from Baseline*

 

Placebo

Etanercept

Placebo

Etanercept

 

Parameter

N = 139

N = 138

N = 139

N = 138

P-value

Tender joints

 

 

 

 

 

Baseline

9 (4)

7 (3)

 

 

 

12 weeks

8 (2)

5 (1)

-1.0 (21)

37 (50)

0.0061

24 weeks

8 (2)

5 (1)

1.4 (31)

36 (62)

0.0014

Swollen joints

 

 

 

 

 

Baseline

4 (0)

4 (1)

 

 

 

12 weeks

4 (0)

3 (0)

-15 (50)

36 (66)

0.1263

24 weeks

3 (0)

2 (0)

-11 (50)

4 (60)

0.8384

* Patients with a count of zero at baseline were not included in the analysis of percent improvement from

baseline. The number of patients with a zero baseline score varied, depending on the parameter of interest.

† P-value determined by Cochran-Mantel-Haenszel row means test with Modridit option on percent

improvement from baseline.

 

 

 

 

 

 

Acute Phase Reactants

 At baseline the acute phase reactants, ESR and CRP were within the normal range in approximately 53% of placebo recipients and 46% of etanercept recipients. The changes in these acute phase reactants during the study demonstrate statistical significant improvement in both at the 12 and 24 week time point (Table 15).  This improvement is also seen in the number of subjects whose values enter the normal range. At 24 weeks of treatment, the number of placebo recipients with ESR and CRP in the normal range was unchanged but the number among the etanercept recipients had increased to approximately 84%.

Table 15 Other Endpoints: Acute Phase Reactants

Acute Phase Reactants

Mean (median) Values and Percent Improvement from Baseline

 

 

Mean (median)

 

 

Mean (median) Values

Percent Improvement from Baseline*

 

Placebo

Etanercept

Placebo

Etanercept

 

Parameter

N = 139

N = 138

N = 139

N = 138

P-value

ESR (mm/hr)

 

 

 

 

 

Baseline

25 (17)

26 (23)

 

 

 

12 weeks

26 (16)

13 (9)

-19 (0)

18 (60)

< 0.0001

24 weeks

26 (19)

11 (7)

-23 (0)

42 (60)

< 0.0001

CRP (mg/dL)**

 

 

 

 

 

Baseline

2 (1)

2 (1)

 

 

 

12 weeks

2 (1)

1 (0.2)

-143 (-5.4)

10 (69)

< 0.0001

24 weeks

2 (1)

<1 (0.3)

-96 (0)

38 (73)

< 0.0001

‡ Erythrocyte sedimentation rate (ESR) normal range: 1–17 mm/hr for men; 1–25 mm/hr for women.

**C-reactive protein (CRP) normal range: 0–1.0 mg/dL.

Assessor Global Assessments

In the same manner as Physician Global Assessments have been used to complement Patient Global Assessments for therapeutic measurements in other rheumatologic disorders, they have been studied in Ankylosing Spondylitis and were analyzed in this study.  As demonstrated in (Table 16), the Assessor Global Assessment showed statistically significant improvement among the etanercept recipients at both the 12 and the 24 week time points.

Table 16 Other Endpoints: Assessor Global Assessments

Assessor Global Assessments

Mean (median) Values and Percent Improvement from Baseline

 

 

Mean (median)

 

 

Mean (median) Values

Percent Improvement from Baseline

 

Placebo

Etanercept

Placebo

Etanercept

 

Parameter

N = 139

N = 138

N = 139

N = 138

P-value*

Assessor’s Global Assessment

 

 

 

 

 

Baseline

57 (58)

54 (57)

 

 

 

12 weeks

48 (50)

33  (30)

10 (14)

34 (45)

< 0.0001

24 weeks

49 (51)

34 (30)

6 (13)

30 (45)

< 0.0001

* P-value determined by Cochran-Mantel-Haenszel row means test with Modridit option on percent improvement from baseline.

 


Exploratory Analysis

 

ASAS DCART 20 and ASAS DCART 40 Exploratory Analysis

Disease-controlling Anti-rheumatic Therapy (DCART) criteria were proposed by an ASAS advisory group for use in AS in discussions held with the FDA. Two alternative endpoint definitions were proposed and this study pre-specified both as exploratory analyses.

The DCART 20 is a composite score that combines the 4 criteria of the ASAS Response Criteria used in the primary efficacy analysis with 2 additional criteria; improvement in chest expansion (spinal mobility) and CRP (acute phase reactants). The ASAS DCART 20 response requires a 20% improvement in 5 or the 6 criteria, with no worsening in the remaining criterion. For the 4 criteria that DCART shares with ASAS Response Criteria, the same rules apply. For the 2 additional criteria, changes in measurements of chest expansion and CRP were based upon 20% improvement or worsening relative to baseline without requirement for absolute numeric change.

The DCART 40 uses the 4 criteria of the ASAS Response Criteria and does not propose any additional criteria. In this instance, a 40% improvement relative to baseline plus absolute improvement of at least 20 units on 3 of the original ASAS criteria with no worsening in the remaining criterion are necessary.

The results of these exploratory analyses are presented in (Table 17). Both the DCART 20 and DCART 40 demonstrated statistically significant improvement of etanercept over placebo at 12 and 24 weeks.

 

Table 17 Exploratory Analysis: Number(%) Achieving ASAS DCART 20 and ASAS DCART 40

Exploratory Analysis: ASAS DCART 20/40

Number (%) Achieving ASAS DCART 20 /40 Responses

 

Placebo

Etanercept

 

DCART-proposed Parameter

N = 139

N = 138

P-value*

ASAS DCART 20 (n [%]) at:

 

 

 

2 weeks

7 (5)

41 (30)

< 0.0001

12 weeks

11 (8)

51 (37)

< 0.0001

24 weeks

10 (7)

46 (33)

< 0.0001

ASAS DCART 40 (n [%]) at:

 

 

 

2 weeks

11 (8)

38 (28)

< 0.0001

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.

 

 

Duration and Attainment Delay of ASAS 20 Response

Measurement of ASAS 20 at both 12 and 24 week permits exploration of response dynamics to include treatment response duration and delay.  As presented in (Table 18) 86% of subjects receiving etanercept who had achieved an ASAS 20 at week12 also had an ASAS 20 response at 24 weeks compared to 66% of placebo. Further, the treatment difference between etanercept and placebo12 week responders continues unchanged at 24 weeks. The percentage of etanercept recipients who lost ASAS 20 response in the 12 weeks between measurements was less than half of that of placebo recipients and the percentage achieving ASAS 20 for the first time was twice as high (15% versus 7%). This suggests that most patients who achieve an ASAS 20 response on etanercept will achieve that response by 3 months.

Table 18 Duration of ASAS 20 and Delay in Attainment of ASAS 20

Exploratory Analysis: Duration of ASAS 20 and Delay in attainment

 

Placebo

Etanercept

Parameter

N = 139

N = 138

ASAS 20 or higher (n [%]) at:

 

 

12 weeks

38 (27)

83 (60)

24 weeks

32 (23)

80 (58)

ASAS 20 at 12 wks also responders at 24wks

25/38 (66)

71/83 (86)

ASAS 20 at both 12/24 wks/ITT population

25/139 (18)

71/138 (51)

Positive to Negative

13/38 (34)

12/83 (14)

Negative to Positive

7/101 (7)

8/55 (15)

 

Exploratory Analysis:  Impact of Gender, Race and Site on ASAS 20

76% of study participants were male and the treatment difference between etanercept and placebo for men is 38% Etanercept also appears to be beneficial for women but the treatment associated difference appears blunted at 17% (Table 19).

The significance of this finding is unknown and may  be due to wider confidence intervals due to the small number of females enrolled. The impact of race upon the ASAS 20 is difficult to assess since only 20 non-caucasians were enrolled. Geographic site did not appear to have a significant impact upon the ASAS 20 treatment response (Table 19).

 

Table 19 Exploratory Analysis: ASAS 20 at 12wks by baseline

 non-disease associated factor

Exploratory Analysis: ASAS 20 Non-disease Associated factor

Baseline Characteristic

Status

Placebo

n/N (%)

Etanercept

n/N (%)

Sex

Male

28/105 (27)

68/105 (65)

 

Female

10/34 (29)

15/33 (45)

Race

Caucasian

36/127 (28)

76/130 (58)

 

Non-Caucasian

2/12 (17)

7/8 (88)

Site

North American

34/109 (31)

63/106 (59)

 

European

4/30 (13)

20/32 (63)

 

 

 

Exploratory Analysis: impact of Age, Weight and Disease Duration upon ASAS 20 at 12 Weeks

Etanercept administration was associated with superior treatment response in all age groups. However, the treatment response appears to decline steadily as age increases from 74% in subjects <34 to 45% in subjects older than 50 years of age (Table 20). Weight did not appear to have a significant impact upon ASAS 20 responses of etanercept. Despite the apparent impact of age upon response, duration of disease did not appear to have a significant impact upon the ASAS 20 with those with a less than 2.25 year duration of illness having the same ASAS 20 as those with those with a greater than 16 year disease duration (Table 20).

Table 20 Exploratory Analysis: ASAS 20 at 12wk by Age, Weight and Duration of Disease

Characteristic

Placebo

N/N (%)

Etanercept

N/N (%)

Whole Population

38/139 (27)

83/138 (60)

AGE

 

 

<34

12/38 (32)

23/31 (74)

34 to <42

6/25 (24)

24/37 (65)

42 to <50

10/35 (29)

23/41 (56)

50+

10/41 (24)

13/29(45)

WEIGHT

 

 

<68kg

9/33 (27)

16/29 (55)

68 to <80kg

9/26 (35)

28/45 (62)

80 to <93kg

10/40 (25)

18/32 (56)

93+ kg

10/39 (26)

20/31 (65)

Disease Duration

 

 

<2.25yrs

16/35 (46)

20/34 (59)

2.25 to <8.75yrs

8/35 (23)

19/34 (56)

8.75 to <16.25yrs

4/31 (13)

25/38 (66)

16.25+ yrs

10/38 (26)

19/32 (59)

 

Exploratory Analysis: Impact of Concomitant Non-Skeletal Inflammatory Disorders upon ASAS 20 at 12 weeks.

Patients with non-skeletal inflammatory disorders associated with Ankylosing Spondylitis such as uveitis as well as conditions associated with other spondyloarthropathies such as psoriasis were enrolled in this study. The impact of these conditions upon ASAS 20 response was explored. History of Uveitis/Iritis, inflammatory bowel disease and risk of reactive arthritis did not appear to have any adverse impact upon the ASAS 20 response to etanercept (Table 21).  

 

 

 

 

 

Table 21 Exploratory Analysis: ASAS 20 at 12 wks in subjects with

Concomitant Non-Skeletal Inflammatory Disorders

Baseline Characteristic

Status

Placebo

n/N (%)

Etanercept

n/N (%)

Hx Uveitis or Iritis

No

26/96 (27)

58/99(59)

 

Yes

12/43 (28)

25/39 (64)

Hx Psoriasis

No

33/124 (27)

78/127 (61)

 

Yes

5/15(33)

5/11(45)

Hx IBD

No

38/133(29)

78/131(60)

 

Yes

0/6(0)

5/7(71)

Hx bacterial dysentery, urethritis

Chlamydia, STD

No

33/126 (26)

76/127(60)

 

Yes

5/13 (38)

7/11(64)

 

Exploratory Analysis: Impact of prior and or concomitant medications upon ASAS 20 at 12 weeks.

The majority of subjects had history of either prior or concomitant medications. Approximately 31% were receiving concomitant DMARDS and the study was stratified to consider DMARD use. Exploratory analysis of the impact of  prior or concomitant medication use did not indicate a significant effect on the ASAS 20 at 12 weeks

 (Table 22). Subjects using NSAIDS appeared to have higher response to etanercept than those without such use but the numbers are small. Of the DMARDS, responses to etanercept were higher among patients receiving concomitant Sulfasalazine compared to other DMARDS. Methotrexate use, however, appeared to be associated with a lower response but again the numbers are small and no definite conclusions can be reached.

 

Table 22 Exploratory Analysis: ASAS 20 at 12 weeks compared with prior/concomitant medications

Baseline Characteristic

Status

Placebo

N/N (%)

Etanercept

N/N (%)

NSAIDS w/i 6mo Screening

No

3/11 (27)

6/12(50)

 

Yes

35/128 (27)

77/126 (61)

Corticosteroids w/i 6mo Scr

No

37/119 (31)

72/120(60)

 

Yes

1/20 (5)

11/18(61)

Concomitant DMARD(s)

No

29/96 (30)

56/94(60)

 

Yes

9/43 (21)

27/44(61)

Concomitant sulfasalazine

No

31/109 (28)

63/109 (58)

 

Yes

7/30 (23)

20/29 (69)

Concomitant methotrexate

No

35/122 (29)

75/123(61)

 

Yes

3/17 (18)

8/15 (53)

 

 

 

 

Exploratory Analysis: Impact of Baseline Disease Severity upon the ASAS 20 at 12 weeks

The impact of baseline disease severity upon the response to etanercept was explored using individual components of the ASAS response criteria and hip involvement, a prognostic factor in ankylosing spondylitis. The superiority of etanercept was preserved for each individual component for both high and low baseline disease severity. There were, however, differences in the magnitude of response and in the treatment difference compared to placebo. For the components of average back pain, patient global assessment, and the last two questions of the BASDAI (inflammation) those demonstrating greater disease severity at baseline had higher percentages of ASAS 20 achievement and wider treatment differences compared to placebo (Table 23). For the BASFI, although the treatment difference is higher in the population with greater disease severity, the percentage achieving ASAS 20 was lower (Table 23).  A possible explanation for these differences may be that the disease severity measured in the first three components has a stronger relationship to inflammation than does the functionality measured in the BASFI.  The presence of hip involvement did not appear to have a significant impact upon the ASAS 20 achievement percentages.

 

Table 23 Exploratory Analysis: ASAS 20 at 12 wks compared with baseline individual disease severity

Baseline Characteristic

Status

Placebo

Etanercept

Average Back Pain-total

£ Median =63

22/65 (34)

40/74 (54)

 

> Median=63

16/74 (22)

43/64 (67)

Patient Global Assessment

£ Median=65

22/74 (30)

39/68 (57)

 

> Median=65

16/65 (25)

44/70 (63)

BASFI

£ Median=53.4

22/61 (36)

50/78 (64)

 

> Median=53.4

16/78 (21)

33/60 (55)

Average last 2 BASDAI

£ Median=62.5

19/65 (29)

43/74 (58)

 

> Median=62.5

19/74 (26)

40/64 (63)

Hip disease or limited ROM of Hip

No

9/31 (29)

27/44 (61)

 

Yes

29/107 (27)

50/85 (59)

 

Further exploration of the relationship between baseline disease severity and the percentage of ASAS response was performed to include further refinement of severity measurement as well as treatment duration. As shown in (Table 24), at 12 weeks, subjects with baseline back pain measured <50 had the lowest ASAS 20 and treatment difference compared with placebo. ASAS 20 and treatment difference percentages do not increase in a strictly linear manner, however.  The highest ASAS 20 and treatment difference percentage were actually found in those with a baseline back pain VAS of between 63 and 76 (Table 24). These findings persist at 24 weeks (Table 24).

 

 

Table 24 Exploratory Analysis: ASAS 20 at 12/24wks by Baseline Back Pain

Baseline

Back pain

Placebo

N/N (%)

Etanercept

N/N (%)

Week 12

 

 

All

38/134 (28)

83/133 (62)

<50

9/26 (35)

19/37 (51)

50 to <63

13/36 (36)

20/32 (63)

63 to <76

9/36 (25)

24/33 (73)

76+

7/36 (19)

20/31(65)

Week 24

 

 

All

32/121 (26)

80/125 (64)

<50

10/24 (42)

19/33 (58)

50 to <63

11/32 (34)

18/29 (62)

63 to <76

7/34 (21)

24/32 (75)

76+

4/31 (13)

19/31 (61)

 

Exploratory Analysis: Impact of HLA B27 upon ASAS Response Criteria

84% of the study population was positive for HLA B27 antigen. Examination of the impact of the presence or absence of this antigen on the ASAS 20/50/70 response rates at 12 and 24 weeks indicate that for the ASAS 20 and ASAS 50 measurements, subjects that were HLA-B27 antigen positive had a better response to etanercept than the entire population (Table 25). Conversely, although consistently higher than placebo in all comparisons, etanercept recipients who were HLA-B27 antigen negative had lower ASAS 20 and 50 response percentages at 12 weeks and 24 weeks compared to those of the HLA-B27 positive patients (Table 25).  The ASAS 70 determinations in etanercept recipients appeared to be approximately the same in the two subpopulations at both times. The explanation for this apparent blunting of the ASAS 20/50 response at 12 and 24 weeks is unknown but it should be kept in mind that only small numbers of HLA-B27 antigen negative patients were enrolled.

Table 25 Exploratory Analysis: ASAS 20/50/70: HLA B27 Known

Secondary Endpoints: Impact HLA-B27

 

HLA B27 Positive

HLA B27 Negative

 

Placebo

 

Etanercept

 

Placebo

Etanercept

 

Parameter

N = 109

N = 108

N = 19

N = 21

ASAS 20 (n [%]) at:

 

 

 

 

12 weeks

31 (28)

70 (65)

5 (26)

8 (38)

24 weeks

26  (24)

67 (62)

3  (16)

9 (43)

ASAS 50 (n [%]) at:

 

 

 

 

12 weeks

14 (13)

53 (49)

3 (16)

6 (29)

24 weeks

11 (10)

49 (45)

2 (11)

7 (33)

ASAS 70 (n [%]) at:

 

 

 

 

12 weeks

7 (6)

33 (31)

2  (11)

6 (29)

24 weeks

5  (5)

31 (29)

2  (11)

6 (29)

 

Safety Analyses

Overview of Adverse Events

Approximately 75% of patients in both study arms experienced one or more adverse events (Table 26). Overall, injection site reactions, accidental injury and infections occurred more frequently in the etanercept arm than in the placebo. The incidence rate for injection site reactions and infections was similar to those reported in the package insert. study drug dose modification was accomplished by skipping administration of scheduled dose. At least one dose of study drug was skipped for adverse events in 3 placebo recipients and 14 etanercept recipients. Infection was the associated adverse event in 1 of 3 placebo and 9 of 14 etanercept recipients. No study drug was skipped for a laboratory abnormality.

Table 26 Adverse Events in ³ 5% of Patients

Adverse Events of All Intensities in ³5% of Patients in Either Treatment Group

 

Proportions of Patients

(n [%])

 

Placebo

Etanercept

Event

N = 139

N = 138

Any adverse event

105 (76)

99 (72)

Infections

42 (30)

57 (41)

Injection site reaction

13 (9)

41 (30)

Injection site ecchymosis

23 (17)

29 (21)

Headache

16 (12)

19 (14)

Accidental injury

6 (4)

17 (12)

Diarrhea

13 (9)

11 (8)

Rash

9 (7)

11 (8)

Dizziness

3 (2)

8 (6)

Rhinitis

9 (7)

8 (6)

Abdominal pain

7 (5)

8 (6)

Nausea

7 (5)

7 (5)

Asthenia

7 (5)

5 (4)

 

The incidence of severe and serious adverse events as well as discontinuations for adverse events were numerically higher in the etanercept arm compared to the placebo arm (Table 27). There were no discontinuations for laboratory abnormalities.

Table 27 Tabulation of Important Safety Outcomes

Safety Outcomes

Placebo

N=139

n/N %

Etanercept

N=138

n/N  %

Serious Adverse Events

5 (4)

9 (7)

Withdrawals for Safety

1(1)

7 (5)

Grade 3/4 Adverse Events/ Infections

4(3)

14 (10)

Grade 3/ 4 Abnormal Laboratory

0 (0)

2*(1)

* 1 Grade 3 Low ANC, 1 Grade 3 Low Lymphocytes

Serious Adverse Events

10 SAE occurred in 9 etanercept recipients and 5 SAE occurred in 5 placebo patients (Table 28). Infections and accidental injury occurred in both study arms but were more frequently encountered among the etanercept patients. Serious infections will be discussed separately. Of the remaining Serious Adverse Events in the etanercept group, one patient developed a febrile reaction with rash suggestive of a hypersensitivity reaction, another developed transient unilateral lymphadenopathy (with equivocal PPD positivity) that resolved without treatment and another patient with a past history of ulcerative colitis developed pancolitis while on treatment that necessitated study discontinuation.

Table 28 Serious Adverse Events

Patient no.

Sex/Age

D/C Date

Cause

Grade

Comments

Placebo

 

 

 

 

 

163

M/45

25

Industrial Accident

3

Hospitalized

245

M/29

164

Viral Infection

2

Hospitalized

268

M/49

141

Suicide Attempt

4

Hx Major Psychiatric Dz

562

M/50

15

MVA back injury

3

D/C LOE

572

F/48

100

Chest Pain

2

Hospitalized w/ recur CP r/oMI

Etanercept

 

 

 

 

 

158

M/53

23

Febrile Reaction

3

3hr p w/rash

167

M/60

141

Lymphadenopathy

2

+/- PPD -INH prophylaxis 

191

M/28

94

Cellulitis insect bite

3

Hospitalization

241

M/43

129

Vertebral Fx MVA

3

Hospitalization

269

M/64

71

Fibular fracture fall

3

Multiple Med-problems

513

M/34

82

Cellulitis cat bite

3

Hospitalized

515

F/49

43

Fx Elbow fall

3

Hospitalized

559

M/44

110

Pancolitis UC

3

Hx IBD switch TNF

580

M/56

144

Intestinal Obstruction

3

Prior Surgery

Adhesions

 

Infections

As previously shown in (Table 28), there were 3 infections that were considered serious, one in the placebo arm and the other two in the etanercept arm. In both instances in the etanercept arm, the serious infections both involved cellulitis associated with an antecedent injury; one an insect bite, the other a cat bite, and both required intravenous antibiotics to control the infection. Staphlococcus aureus was recovered in the insect bite cellulitis, the presumed bacterial cause of the cat bite related cellulitis was not recovered.

Infections of all intensities were more common in etanercept recipients. The predominant cause appears to be the greater incidence of upper respiratory tract infections (Table 29).

Table 29 Infections of All Intensities in ³ 5% of Patients

Infections of All Intensities in ³

5% of Patients in Either Treatment Group

 

Proportions of Patients

(n [%])

 

Placebo

Etanercept

Event

N = 139

N = 138

Any infection

42 (30)

57 (41)

Any infection except URI

28 (20)

33 (24)

Upper respiratory infection

16 (12)

28 (20)

Flu syndrome

10 (7)

5 (4)

 

 

If patients treated with oral or parenteral systemic antimicrobials are compared between etanercept and placebo, the important contribution of bacterial causes to the increased incidence of URI becomes apparent (Table 30). Dental infections and sinusitis in particular appeared to be numerically more prevalent among etanercept recipients than in placebo recipients.

 

Cellulitis requiring antibiotics was also more prevalent in the etanercept group but the numbers were small, the higher incidence of intravenous antibiotics in the etanercept group was largely caused by 3 SAE: the two serious infections (previously mentioned) and the patient with exacerbation of ulcerative colitis (Table 30).

Table 30 Infections Requiring Oral or Parenteral Systemic Antimicrobials

Infections Requiring Oral or Parenteral Systemic Antimicrobial Therapy (AMT)

Placebo

n/N  %

Etanercept

n/N %

Total number of subjects receiving AMT/ Total Study Population

21/139 (15)

27/138 (20)

URI/Dental/Sinusitis/Otitis Media

9/21 (43)

14/27 (52)

Bronchitis/Pneumonia

3/21 (14)

3/27 (11)

UTI or GYN

3/21 (14)

3/27 (11)

Cellulitis

1/21 (5)

3/27 (11)

GI/Colitis

1/21 (5)

2/27 (7)

Antibiotic Prophylaxis

4/21 (19)

4/27 (15)

IV Antibiotics

0/21 (0)

3/27 (11)

 

Study Withdrawals for Safety

There was one withdrawal from study for safety in the placebo arm compared to seven withdrawals in the etanercept arm (Table 31). There is overlap between safety withdrawals and patients with SAE since some of these were discontinued. Of the seven withdrawals in etanercept recipients, 4 were for bowel related. One of these was a bowel obstruction secondary to surgical adhesions, the other three were for symptoms suggestive of inflammatory bowel disease (IBD). One episode occurred in an individual with medical history suggestive of IBD prior to enrollment, the other two did not give a history of IBD prior to enrollment but upon questioning, had histories that were suggestive of IBD. Two of the three episodes were diagnosed as inflammatory bowel disease, one was a recurrence in the previously diagnosed patient, and the other was a new diagnosis. The third patient was evaluated and colonoscopic evaluation did not reveal IBD; his diarrhea was attributed to study drug with hemorrhoidal bleeding. Of the 6 individuals with history of IBD prior to enrollment in the placebo arm, none were withdrawn for flare of IBD. Of the 7 individuals in the etanercept arm with a history consistent with IBD prior to enrollment, 3 developed bloody diarrhea of sufficient severity to withdraw from study, two diagnosed as having a flare of IBD.

 Table 31 Study Withdrawals for Safety

Patient no.

Sex/Age

D/C Date

Cause

Grade

Comments

Placebo

 

 

 

 

 

268

M/49

141

Suicide Attempt

4

Hx Major Psychiatric Dz

Etanercept

 

 

 

 

 

123

M/30

29

LGI Bleed Hemorr Negative IBD

2

Hx c/w IBD

158

M/53

23

Febrile Reaction

3

3hr p w/rash

241

M/43

129

Vertebral Fx MVA

3

Surgical Intervention

253

M/54

54

Ileitis from Crohns

1

Hx IBD switch TNF

269

M/64

71

Fibular fracture fall

3

Multiple Med-problems

559

M/44

110

Pancolitis UC

3

Hx IBD switch TNF

580

M/56

144

Intestinal Obstruction

3

Prior Surgery

Adhesions

Grade 3 and 4 Adverse Events not considered to be SAE

6 patients, one in the placebo arm and the other 5 in the etanercept arm developed Grade 3 Adverse Events (there were no grade 4) (Table 32). Two in the etanercept arm and one in the placebo experienced elevated blood pressure, one in each arm due to changes in pre-study anti-hypertensives, the remaining etanercept patient developed hypertension for the first time which was easily medically managed.  The two remaining etanercept patients developed severe neurologic adverse events; one a 12 day migraine headache (prior history of migraines) and the other a grand mal seizure which was ultimately attributed to a abrupt withdrawal from chronic lorazepam and oxycodone administration. seizures are mentioned in the current package insert under Warnings, neurologic.

Table 32 Grade 3/4  Adverse Events/Infections Not SAE

Patient no.

Sex/Age

D/C Date

Cause

Grade

Comments

Placebo

 

 

 

 

 

119

F/52

 

hypertension

3

Change in Hypertension Rx

Etanercept

 

 

 

 

 

126

F/30

35

Migraine x12days

3

Completed Study

238

M/32

59

Gran Mal SZ

3

Abrupt d/c Valium 

253

M/54

94

Hypertension

3

Change in Hypertension Rx