Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Inflammation Suppression Over 24 Weeks in Patients with Gouty Arthritis: Results From Two Phase-III Core and Extension Studies Comparing Canakinumab with Triamcinolone Acetonide.

So1,  A., Alten2,  R., Schumacher3,  H. R., Bardin4,  T., Bloch5,  M., Richard6,  D., Karpov6,  A.

CHUV, Lausanne, Switzerland
Charité Teaching Hospital–Schlosspark-Klinik, Berlin, Germany
University of Pennsylvania and VA Medical Center, Philadelphia, PA
Hôpital Lariboisière, Paris, France
Holdsworth House Medical Practice, Sydney, Australia
Novartis Pharma AG, Basel, Switzerland
UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ

Background/Purpose:

Gouty arthritis (GA) is a chronic inflammatory arthritis, mainly driven by IL-1b—a proinflammatory cytokine. Canakinumab, a fully human monoclonal anti-IL-1b antibody, offers a new therapeutic option for GA that may provide significant long-term benefits.

Methods:

In two, pivotal 12-week, multicenter, double blind, double dummy, active-controlled studies (b-RELIEVED and b-RELIEVED-II), GA patients (meeting preliminary ACR-1977 criteria) with flare duration <=5 days and unresponsive, intolerant or contraindicated to NSAIDs and / or colchicine were randomized to receive a single dose of canakinumab 150mg sc or triamcinolone acetonide (TA) 40mg im and were re-dosed "on demand" on each new flare. Patients completing the core studies were enrolled into 12-week extension studies to further investigate "on demand" use of canakinumab 150 mg sc or TA 40 mg im on new flare. Inflammatory markers (CRP, SAA), tenderness and swelling were assessed at baseline, 72h and 7 days post dose, 12, and 24 weeks, where as IL-6 and TNF-a was assessed at baseline, 12 and 24 weeks.

Results:

In both core studies, 454 patients received treatment and 416 completed the studies. Of these, 335 patients entered and 317 completed the extension studies. At baseline in b-RELIEVED and b-RELIEVED-II, 17.1% and 16.8% had polyarticular GA and the mean number of flares in the previous year was 6.8 and 6.2, respectively. A large proportion (60.5%; 60.2%) of patients had a history of GA >5 years. Median CRP and SAA levels were elevated at baseline (Table). Following treatment with canakinumab, CRP decreased rapidly and normalized by 7 days post dose and SAA normalized by 3 days post dose. Both remained below upper limit of normal (ULN) over 24 weeks. Following treatment with TA, CRP remained above ULN at all post-dose time points except 24 weeks and SAA remained above ULN until Week 12. IL-6 was more effectively suppressed with canakinumab than TA over 24 weeks. No major changes in levels of TNF-a were observed, demonstrating its lack of involvement in this inflammatory cascade.

Table. Changes from baseline in inflammatory markers at 72 h, 7 days, 12 and 24 weeks post dose by treatment group

 Canakinumab N=113TA=115
b-RELIEVED Median (range)Baseline72 h7 days12 WK24 WK (EOS)Baseline72 hrs7 days12 WK24 WK (EOS)
CRP levels, ULN=3.0mg/L(n=110) 13.2 (0–346)(n=112) 4.4* (0–62)(n=113) 2.1* (0–70)(n=105) 1.8 (0–47)(n=85) 2.6 (0–90)(n=113) 9.4 (1–278)(n=109) 5.2 (0–198)(n=104) 3.6 (0–305)(n=100) 3.8 (0–64)(n=76) 3.0 (0–79)
SAA levels, ULN=6.7mg/L(n=113) 18.0 (1–2500)(n=108) 5.2* (0–444)(n=111) 3.3* (0–202)(n=102) 3.5 (0–70)(n=85) 4.0 (0–198)(n=113) 9.9 (0–1080)(n=109) 10.1 (1–768)(n=109) 7.9 (4–1280)(n=100) 6.2 (1–179)(n=75) 6.1 (0–210)
IL-6 levels(n=80) 4.6# (0–356)NANA(n=80) 0 (0–131)(n=96) 2.7** (0–38)(n=73) 4.80# (0–143)NANA2.7 (0–75)3.5** (0–61)
 (n=96) 4.1̂ (0–356)    (n=96) 3.8̂ (0–143)    
 Canakinumab N=112TA (N=114)
b-RELIEVED-IIBaseline72 h7 days1224 WK (EOS)Baseline72 hrs7 days12 WK24 WK
CRP levels, ULN=3.0mg/L(n=112) 10.2 (0–350)(n=107) 4.3* (0–73)(n=108) 1.8* (0–92)(n=97) 1.4 (0–46)(n=79) 1.6 (0–89)(n=114) 8.9 (0–227)(n=110) 7.0 (0–225)(n=109) 3.1 (0–98)(n=97) 3.2 (0–62)(n=70) 2.7 (0–30)
SAA levels ULN=6.7mg/L(n=106) 11.2 (0–2070)(n=106) 5.1* (0–952)(n=105) 2.9* (0–1070)(n=92) 3.5 (0–109)(n=77) 3.4 (0–180)(n=112) 9.8 (0–2160)(n=107) 11.1 (0–1940)(n=108) 7.3 (0–908)(n=96) 4.5 (1–380)(n=70) 5.5 (0–158)
IL-6 levels(n=81) 3.30# (0–188)NANA0.0 (0–86)0** (0–53)(n=68) 1.0# (0–370)NANA2.4 (0–117)0** (0–177)
 (n=92) 2.75̂ (0–188)    (n=98) 3.0̂ (0–370)    
* denotes p <0.0001; ULN: upper normal limit,**24 weeks (EOS) in case patient discontinued prior to 24 weeks, levels for IL6 measured at discontinuation visit was included
# baseline statistics in patients who had both baseline and 12 week values
̂ baseline statistics in patients who had both baseline and 24 wk (EOS) values

Patients in the canakinumab group had less tenderness and swelling (b-RELIEVED OR: 2.00, 2.25; 1.72, 2.02 at 72 h and 7 days; b-RELIEVED-II OR: 2.34, 2.07; 1.76, 1.21, at 72 h and 7 days post dose) compared to the TA group.

Conclusion:

IL-1b blockade with canakinumab provided significant and sustained anti-inflammatory benefit over 24 weeks that was consistent with the clinical improvement in pain and significant delay in subsequent flares. Longer persistence of higher levels of inflammatory markers in the TA group suggests less control of ongoing inflammation.

To cite this abstract, please use the following information:
So, A., Alten, R., Schumacher, H. R., Bardin, T., Bloch, M., Richard, D., et al; Inflammation Suppression Over 24 Weeks in Patients with Gouty Arthritis: Results From Two Phase-III Core and Extension Studies Comparing Canakinumab with Triamcinolone Acetonide. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1019
DOI:

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