A randomized, double-blind, placebo-controlled phase III multicenter study of subcutaneous secukinumab in prefilled syringes to demonstrate the efficacy at 16 weeks and to assess the long-term efficacy, safety and tolerability up to 5 years in patients with active Ankylosing Spondylitis (CAIN457F2310)

Ankylosing spondylitis (AS) is a chronic inflammatory disease, which is mainly
characterized by involvement of axial joints and bilateral sacroiliitis. It
affects up to 0.9% of the population and is associated with significant
morbidity and disability, and thus constitutes a major socioeconomic burden.
Sometimes peripheral joints and extra-articular organs are involved as well.
Associated extra-articular manifestations include acute anterior uveitis,
cardiovascular and pulmonary abnormalities, neurologic sequelae, and both
clinical and subclinical gastrointestinal findings. Decreased bone mineral
density is typical of extra-articular symptoms and many patients with AS have
osteoporosis.
The first-line drug treatments of mild AS are NSAIDs. Treatment of
NSAIDs-refractory AS is hampered by the lack of efficacy of virtually all
standard disease modifying anti-rheumatic drugs including methotrexate. TNF
blocking demonstrated prolonged efficacy up to three years of follow-up, but
upon discontinuation of TNF blockers the disease relapses quickly. Observations
so far indicate that other treatments are needed to treat patients who do not
respond to TNF blockers and/or who have incomplete resolution of inflammatory
changes as evidenced on MRI studies.
Interleukin-17 antagonism by secukinumab represents a novel approach to
interfere with the chronic inflammatory process. Notably secukinumab showed
good efficacy in patients with AS. This is based upon an interim analysis of
the ongoing Proof of Concept study, in which the ASAS20 response rate at week 6
was achieved by approximately 60% of the patients.
The purpose of the present 5 year study is to demonstrate the efficacy on signs
and symptoms at Week 16 and to assess the long term safety, tolerability and
efficacy of secukinumab given as s.c. injections (prefilled syringes) of 2 dose
levels of secukinumab versus placebo in subjects with active AS.

Primary: To demonstrate the efficacy of one or both secukinumab regimens at
Week 16 is superior to placebo in patients with active AS based on the
proportion of patients achieving an ASAS 20 response in the subgroup of
patients who are TNF* inhibitor naïve.
Secondary (key only): ASAS20 week 16 response in the whole study population.
ASAS40 week 16 response in the subgroup and whole study population. Safety and
tolerability.

Multicenter randomized double-blind phase III parallel-group placebo-controlled
study.
Randomisation (1:1:1) to:
* Secukinumab 75 mg (s.c. injections every 4 weeks) *)
* Secukinumab 150 mg (s.c. injections every 4 weeks) *)
* Placebo.
*) after loading period of 4 week with weekly injections.
Screening period of max. 10 weeks. Treatment period approx. 5 years. Follow-up
period 12 weeks.
Evaluation of efficacy at week 16. Patients on placebo will be switched at
week 16 to secukinumab (randomized allocation of dose (75 or 150 mg
secukinumab).
After Interim Analysis week 52 data: Unblinding; open-label treatment (75 of
150 mg secukinumab).
After approval protocol version 02: Possibility to increase dose form 75 mg to
150 mg secukinumab if therapeutic response is not fully achieved with the
current dose of 75 mg and may improve with a higher dose (judged by
investgator).

Independent DSMB.

Approx. 220 patients.

Until week 16: treatment with secukinumab (75 of 150 mg) or placebo,
doubleblind.
As of week 16: treatment with secukinumab (75 of 150 mg), doubleblind.
After interim analysis week 52 data: Treatment secukinumab (75 of 150 mg),
open-label.
After approval protocol version 02: Possibility to increase dose form 75 mg to
150 mg secukinumab if therapeutic response is not fully achieved with the
current dose of 75 mg and may improve with a higher dose (judged by
investgator).

Risk: Adverse effects of study medication.
Burden: Study duration approx. 5 years. Approx. 44 visits: every 4 weeks (1st 4
visits 1 week apart) during year 1-2, every 12-16 week during year 3-5. Fasting
13x. Duration 2-3 h.
Approx. 85 s.c. injections every 4 weeks (1st 4 weeks: weekly).
Physical examination approx. 35 times.
Blood tests approx. 35 times, 5-30 ml/occasion.
Optional pharmacogenetic/-genomics blood test (10 ml).
ECG every 6 months.
TBC skin test 1x.
Chest X ray 1x (if not performed in previous 3 months).
Visual analogue scales: disease activity, pain, BASFI, BASDAI, EQ-5D,
FACIT-Fatigue, SF-36, WPAI-GH. Per visit 3-7 questionnaires (plus 2x 1 VAS).
Once every 1-3 months.