Department of Health & Human Services Public
Health Service
Food
and Drug Administration
Memorandum Center
for Biologics Evaluation and Research
1401
Rockville Pike
Division of Clinical Trial Design and Analysis
HFM-582
Date:
Advisory Committee Meeting
Clinical Review Briefing Document
STN 103795 / 5123
Etanercept for the Treatment of Ankylosing Spondylitis
Applicant: Immunex, Inc.
TABLE OF CONTENTS
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
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.
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
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
ASAS Response Criteria (ASAS 20) at 12 weeks defined as follows:
· 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)
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:
- 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
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
Components of Other AS Instruments
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.
Statistical Analyses
Primary efficacy analysis
Secondary analyses:
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 |
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) |
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. |
|||
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. |
||||||
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. |
|
||
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) |
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) |
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
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 |
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 |