A randomized, controlled extension study of CACZ885H2357 on the treatment and prevention of gout flares in patients with frequent flares and for whom NSAIDs and/or colchicines are contraindicated, not tolerated or ineffective (CACZ885H2357E1)

Gout is the most common form of inflammatory joint disease in men over the age
of 40 years . It is estimated to affect 0.5-2.8% of men, with a lower rate of
occurrence among women, who experience gout, primarily, after menopause. The
most common clinical finding in these patients is a sudden onset of an acute
gout flare (also referred to as acute gout attack), which is a severe arthritis
(monoarticular/ oligoarticular/ polyarticular) in any joints in the body,
predominantly seen in a peripheral joint in the leg.
Several lines of evidence suggest that gout inflammation is primarily IL-1β
driven and therefore, inflammation in gout may be significantly attenuated with
a selective blockade of IL-1β. In line with this, anakinra, an IL-1 receptor
antagonist, significantly relieved the pain of acute gout flares in patients
who could not tolerate or had failed standard anti-inflammatory therapies for
gouty arthritis. Moreover, rilonacept (IL-1 trap), an IL-1 inhibitor decreased
the disease activity and pain in patients with chronic active gout and also
reduced the occurrence of new gout flares that are often seen during initiation
of urate-lowering therapy.
Canakinumab (ACZ885) is a fully human monoclonal anti-human IL-1β antibody. It
is designed to bind to human IL-1β and thus blocks the interaction of this
cytokine with its receptors. This results in neutralized bioactivity of IL-1β,
but does not prevent the binding of the natural inhibitor, IL-1Ra, nor binding
to IL-1α. Detailed background information on the chemistry, pharmacology,
toxicology, preclinical and clinical data of canakinumab is also given in the
Investigator*s Brochure. Results of a single-dose, 8-week Phase II study
(CACZ885H2255) in gout patients that were refractory and/ or contraindicated to
NSAIDs and/ or colchicine indicated that canakinumab at the selected dose of
150 mg subcutaneously (s.c.) was more effective in treating patient*s pain at
the time of acute gout flares and also in preventing the occurrence of new gout
flares as compared to triamcinolone acetonide 40 mg intramuscularly (i.m.).
This is a first follow-up study, open to patients who have successfully
completed the study CACZ885H2357 (canakinumab vs triamcinolon acetonide, 12
weeks). Thereafter patients may be eligible to enter a 2nd open non-comparative
follow-up study with only canakinumab. This 2nd study is not part of this
submission.

Primary: Longterm safety and tolerability.
Secondary: Time to 1st flare, number and severity of flares, efficiacy in
treating flares, effect on inflammatory markers, immunogenicity, PK.

Multicenter randomized double blind phase III parallel group study.
Patient remains in the randomization group the preceding study:
1. Canakinumab 150 mg s.c.,
2. Triamcinolon acetonide 40 mg i.m.
This study medication will only be administered in case of a gout flare.
Study duration 12 weeks.
Pain killer to be used if needed: paracetamolmol (max. 3 g daily) or codeïne
(max. 180 mg daily) , s.n. prednisolon.
150-200 patients.

Treatment with canakinumab or triamcinolon acetonide in case of gout flare.

Risk: Adverse effects of study medication.
Burden: 3 visits in 12 weeks (NB 1st visit = last visit of preceding study).
All visits: fasting, blood tests (approx 20 ml/visit, total volume: 65 ml) and
questionnaires (VAS, Likert scale, global evaluation, gout questionnaire,
EQ-5D, HAQ-DI or SF-36, work-productivity questionnaire; estimated completion
time 15-20 minutes per visit. In case of flare and study drug administration
3-4 visits and 80 mls of blood extra.
In addition: Physical examination (3x), ECG (2x), pregnancy test (2x), diary
(use of pain killers, symptoms).
In selected centres: Doppler examination joints (2x).