A phase III, randomized, double-blind, placebo-controlled multicenter study of subcutaneous secukinumab in autoinjectors, to demonstrate efficacy at 24 weeks and to assess the long term safety, tolerability and efficacy up to 3 years in subjects with active Psoriatic Arthritis (CAIN457F2318)

About 10 - 40% of patients with psoriasis suffer from psoriatic arthritis
(PsA). PsA is associated with significant morbidity and disability, and thus
constitutes a major socioeconomic burden. The majority of patients will have
psoriasis prior to the occurrence of the associated arthritis and are typically
under treatment for their skin disease. For musculoskeletal disease
manifestations initially NSAIDs are used to alleviate symptoms. Typically
DMARDs are used for PsA including methotrexate, sulfasalazine, cyclosporine,
and leflunomide, however, these are often inadequate because they only
partially control established disease. TNF blocking therapy was successfully
introduced to the treatment of patients with PsA. Despite these efforts, an
unmet clinical need exists for patients with PsA for better disease control and
long term prevention of structural damage beyond mere abrogation of
inflammatory processes. Thus, current treatment options for patients with
intolerance or an inadequate response to anti-TNF-* agents are limited.
Interleukin-17 antagonism by secukinumab represents a novel approach to
interfere with the chronic inflammatory process.
A proof-of concept study conducted in patients with PsA suggests that a
clinically meaningful response
is induced as early as 2 weeks after start of secukinumab treatment, with
further improvement up to Week 6 and maintenance of response up to Week 16.
Therefore, treatment with secukinumab may also reduce loss of cartilage and
erosion of bone in PsA. Furthermore, in a completed proof of concept study, the
effects of secukinumab administered as a single intravenous infusion were
compared with that of placebo in subjects with active plaque-type psoriasis.
The study demonstrated efficacy at the 4- week endpoint and continuous efficacy
at 12 weeks.
The purpose of the present 3 year study is to demonstrate the efficacy at Week
24 (and up to week 52) and to assess the long term safety, tolerability and
efficacy of secukinumab given as s.c. injections (auto-injector) of 2 dose
levels of secukinumab versus placebo in subjects with active PsA.

Primary: To demonstrate that the efficacy of secukinumab 150 mg s.c. or 300 mg
s.c., at Week 24 is superior to placebo based on proportion of subjects
achieving ACR20 response in subjects with active PsA.
Secondary:
- PASI75 week 24
- PASI90 week 24
- DAS28-CRP week 24
- SF-36-PCS week 24
- HAQ-DI week 24
- ACR50 week 24
- Efficacy week 24 based on:
- dactylitis in the subset of subjects who have dactylitis at bsl
- enthesitis in the subset of subjects who have enthesitis at bsl
- Safety and tolerability

Multicenter randomized double-blind phase III parallel-group placebo-controlled
study.
Randomization (1:1:1) to:
* Secukinumab 150 mg (s.c. injections every 4 weeks) *)
* Secukinumab 300 mg (s.c. injections every 4 weeks) *)
* Placebo.
*) after loading period of 4 week with weekly injections.
Evaluation of efficacy at week 24. Patients on placebo will be switched to
secukinumab (randomized allocation of dose) at week 24 (or in case of
inadequate improvement already at week 16).
After approval and implementation of Amendment 2, subjects previously treated
with secukinumab 150 mg will receive 300 mg, as deemed appropriate by the
investigators. When dose escalation has been performed for a given subject, no
dose reduction can be performed at a later stage.
Open-label continuation after year 1.
Screening period of 4-10 weeks (depending on the need for washout of existing
medication). Treatment period up to 3 years. Follow-up period 12 weeks.
Patients are encouraged to inject themselves with an auto-injector. During year
2 and 3 option for injections at home (with reduced hospital visit frequency).
Independent DSMB.
Approx. 405 patients.

Treatment with secukinumab or placebo.

Risk: Adverse effects of study medication.
Burden: Study duration max 3 years. At least 30 visits (basis: auto-injection
at home during year 2 and 3). 9 fasting visits. Visit duration 2-3 h.
In year 1: 34 s.c. injections (NB: double blind, double-dummy design), in year
2 plus 3:25-50 injections (NB: open-label; secukinumab 300 mg group: 2
injections/occasion).
Physical examination 28 times in 3 years.
Blood tests 28 times in 3 years, 5-15 ml/occasion.
Optional pharmacogenetic/-genomics blood test once (10 ml).
ECG 7 times in 3 years.
Chest X ray 1x (if not performed in previous 3 months).
7 questionnaires and 4 visual analogue scales at least 11 times in 3 years.