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Achievement of a Patient Acceptable Symptom State (PASS) and of a Minimum Clinically Important Improvement (MCII) with etanercept in advanced ankylosing spondylitis Results of a double-blind, placebo-controlled study (SPINE)

THU 0348

M. Dougados , J. Braun , S. Szanto , B. Combe , M. Elbaz , P. Geher , V. Leblanc , I. Logeart . 1

2

3

4

5

6

7

7

1 Paris-Descartes

Univ, Cochin Hospital, Paris, France, 2 Ruhrgebiet Univ, Herne, Germany, 3 Univ of Debrecen, Debrecen, Hungary, 4 Lapeyronie Hospital, Montpellier, France, 5 Medical Center Avignon, France, 6 Polyclinic of the Hospitaller Brothers of St. John of God, Budapest, Hungary, 7 Pfizer France, Paris La Défense, France

■ Main concern for patients with ankylosing spondylitis (AS) is progression of disease towards ankylosis and abnormal fixed attitudes1. ■ Patients with advanced spinal ankylosis (i.e., bamboo spine) experience significantly more functional impairment compared with other patients with AS2. ■ TNF blockers have dramatically improved the condition of the patients suffering from an active inflammatory spinal disease activity3,4,5,6 but most of these studies excluded patients with total spinal ankylosis3,4. In addition, other studies performed in these patients were either not controlled, or with a too small sample size7,8,9. ■ Etanercept (ETN) is a recombinant fully human tumor necrosis factor (TNF) soluble receptor that binds with free and membrane-bound TNF. Etanercept has demonstrated efficacy in AS resulting in effective, well-tolerated and sustained reduction of the clinical signs and symptoms3 .

Baseline characteristics

Outcome measures ■ BASDAI ■ BASFI ■ BASMI ■ Total back pain ■ Patient Acceptable Symptom State (PASS):

■ Minimum Clinically Important Improvement (MCII): “Compared to when you started the study, how have you been during the last 48 hours?” “If you answer “improved” at the previous question, how important is this improvement to you?”

Statistical analysis Populations of analysis ■ Clinical efficacy and safety populations: modified ITT (all randomized patients who received at least one dose of blinded test article) Statistical methods ■ Main criterion: Normalized net incremental area under the curve (AUC) for the BASDAI between baseline and W12: – Area between the baseline and the BASDAI curve as a function of time (trapezoidal method) divided by the time the patient remained in the study

OBJECTIVES

Sample size calculation

■ To evaluate the effect of etanercept on symptoms (pain, function), on signs (spinal mobility) and on patients global opinion (PASS and MCII) in patients with active, severe and advanced ankylosing spondylitis.

– Expected difference between groups in the normalized net incremental AUC for BASDAI=15 (SD=20) – Power of 90% and 2-sided Type I error of 5%

■ Secondary criteria: – Changes from baseline in BASDAI, BASFI, BASMI, Total back pain. – Time to reach a sustained PASS using the Kaplan Meier survival analysis and Log-Rank test – MCII – ASAS responses, BASDAI 50

METHODS Study design: 12-week, European (FRA, GER, NLD, HUN), randomized, double-blind, placebo-controlled study

Treatment group Placebo (n=43)

Etanercept

48±10

46±11

91 23±11 86

95 19±10 79

Age, years Male gender, % Disease duration, years B27 positive, % Past history or present symptoms, % Peripheral arthritis Enthesiopathy Uveitis Psoriasis Spinal radiological stage, n (%) II III IV V Radiological mSASSS (0-72) BASDAI (0-100 VAS) BASFI (0-100 VAS) BASMI Total back pain

Randomization

Screening n=95

Randomized n=82 W2

W4

W8

1. Ankylosing Spondylitis 2. Axial 3. Active 4. Advanced and severe 5. Refractory

(mm) 0

W4

-7.8

-5

W8

-10.0

% patients 80

W12

Etanercept n=39 • Lack of efficacy, n=2 • Consent withdrawn, n=1 • Lost to follow-up, n=1

-8.2

-15

Placebo (n=43)

-12.4

-20

*p=0.039

-25

-19.8

-21.6

-30

Completers n=39

67 30

** p=0.004

31

30

20

33

28

21

W4

W8

W12

W2

5

5

2

2

W4

W8

W12

Placebo (n=43)

W2

W4

-0.17

W8

W12 -0.20

-0.18

-0.23

Etanercept (n=39) Etanercept: censored data

Placebo (n=43) Placebo: censored data

60

-0.20

40

-0.30

REFERENCES

Survival analysis of time to achieve a sustained PASS

% patients 100 achieving a sustained 80 PASS

Adjusted mean (±SEM)

p=0.0009 (log-rank test)

Etanercept (n=39)

-0.40

*p=0.011

-0.37

-0.60 -0.70

0

-0.57

-0.57

Time (weeks)

0

** p=0.008

(mm) 0

W2

2

4

6

8

10

12

9 patients in the placebo group and 22 patients in the etanercept group reported a sustained PASS. In the etanercept group, the median time to reach this status was 8 weeks (95% CI: 3.9; NE)

Efficacy: MCII

-15

*p=0.019

-11.0

% patients 80

W8

-14.4

-10

-15.8

63.2

-14.9

-15

-15.4

-25

-18.9

*p=0.023

-28.2

-35

-19.8

-29.2

0

** p=0.010

(mm) 0

W2 -7.4

W4 -12.0

W8 -13.5

W12

-25 -30 -35

60

-14.3

20

Placebo (n=43)

-18.4

*p=0.008

-26.1

-26.4

** p=0.005

0

W8

Placebo (n=43)

W 12

*p=0.025 **p<0.001

9. van der Heijde D et al, for the ATLAS study group. Adalimumab effectively reduces the signs and symptoms of active ankylosing spondylitis in patients with total spinal ankylosis. Ann Rheum Dis 2008;67:1218-21.

28.2

23.3

the trial and all investigators and

Placebo (n=43)

22.3

16.3

W4

Etanercept (n=39)

Etanercept (n=39)

medical staff of all participating centers. This study was sponsored by Wyeth Pharmaceuticals France.

9.3 W2

6. Heiberg MS et al. The comparative effectiveness of tumor necrosis factor-blocking agents in patients with rheumatoid arthritis and patients with ankylosing spondylitis: a six-month, longitudinal, observational, multicenter study. Arthritis Rheum 2005;52:2506-12.

We thank all patients who participated in

46.2

41.0 23.1

Etanercept (n=39)

W4

No unexpected adverse event

-14.4

5. van der Heijde D et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2006;54:2136-46.

8. Rudwaleit M, et al. Adalimumab is effective and well tolerated in treating patients with ankylosing spondylitis who have advanced spinal fusion. Rheumatology 2009;48:551-7.

20.0

W2

4. van der Heijde D al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 2005;52:582-91.

7. Cheung PPM et al. Infliximab in severe active ankylosing spondylitis with spinal ankylosis. Int Med J 2008;38:396-401.

37.8

35.9

3. Davis JC et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 2003;48:3230-6.

Safety

40

-15 -20

% patients with at least 50% improvement

31.0

Etanercept(n=39)

Efficacy: BASDAI 50

Efficacy: BASDAI (2)

20

Placebo (n=43)

52.6

50.0

40 Etanercept (n=39)

-20

75.0

W12

-30

-20 -25

Patients with moderate or very important improvement

60

-11.8

-5 Etanercept (n=39)

W4

1. Dougados M, Landewé R. Spondyloarthritides: pathogenesis, clinical aspect and diagnosis in EULAR compendium on rheumatic disease, Bijlsma J. ed., BMJ Publishing group, 2009;pp 92-116. 2. Boonen A, van der Linden SM. The burden of ankylosing spondylitis. J Rheumatol 2006;33(suppl 78):4-11.

20

Placebo (n=43)

-0.27

-0.50

This study, the first prospective placebo-controlled trial specifically designed in advanced active ankylosing spondylitis demonstrates a statistically significant efficacy of etanercept over placebo on main signs, symptoms and shows the achievement of PASS and MCII addressing therapeutic success at patient level.

Efficacy: PASS

Absolute change from baseline

-0.10

7 8

0

Etanercept (n=39)

0

15

10

W2

Efficacy: BASMI

p=0.046 p=0.014 21

41

40 20

-35

Adjusted mean (±SEM)

-10

Completers n=38

40

0

Adjusted mean (±SEM)

-5

• Adverse event, n=1

p=0.001 p=0.003

60

Absolute change from baseline

Placebo n=43

% patients

Etanercept (n=39)

-10

A SA S 5/6

64

-10.1

-11.6

Absolute change from baseline

Adjusted mean (±SEM)

Modified New-York criteria Overall level of AS neck, back or hip pain ≥ 30 BASDAI ≥ 40 At least 2 lumbar or 3 dorsal or 2 cervical intervertebral adjacent bridges and/or fusion At least 2 NSAIDs at maximum tolerated dose for >3 months

W2

Primary endpoint: Normalized net incremental AUC between baseline and W12

W12

Key inclusion criteria

Adjusted mean (±SEM)

Efficacy: Total back pain

Efficacy: BASDAI (1)

Placebo (n=43)

• BASDAI <40, n=4 • Withdrawn consent, n=4 • No spinal ankylosis, n=2 • Prior anti-TNF intake, n=1 • Hepatitis C, n=1 • Age >70 years, n=1

A SA S 20

(mean±SD)

Flow chart

Etanercept 50 mg/week (n=39)

0

7 (18) 21 (54) 7 (18) 4 (10) 34±22 64±12 63±20 5.7±1.4 70±16

3 (7) 26 (60) 9 (21) 5 (12) 39±19 58±15 57±19 5.8±1.3 61± 20

-5

n=13

n=82

46 28 33 10

44 42 28 12

-10

Screening phase (<6 weeks)

(n=39)

Absolute change from baseline

(mm) 0

Placebo (n=43)

Efficacy: ASAS responses

Efficacy: BASFI

Characteristics

“If you were to remain in the next several months as you were during the last 48 hours, would this be acceptable for you?”

CONCLUSION

R E S U LT S

METHODS (continued)

BACKGROUND

W8 Placebo (n=43)

W12

*p=0.031

All adverse events (%)

28 (65.1)

24 (61.5)

Related adverse events (%)

13 (30.2)

10 (25.6)

Serious adverse events (%)

1 (2.3)

2 (5.1)

Presented at EULAR (EUropean League Against Rheumatism) Roma, June 16-19, 2010


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