A randomized, double-blind, placebo-controlled, multicenter study of secukinumab to demonstrate the efficacy at 16 weeks and to assess the long term safety, tolerability and efficacy up to 2 years in patients with active Ankylosing Spondylitis

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 2 year study is to demonstrate the efficacy on signs
and symptoms at Week 16 and to assess the long term safety, tolerability and
efficacy on signs, symptoms and spine structure of secukinumab given as i.v.
loading doses, followed by s.c. injections of 2 dose levels of secukinumab
versus placebo in subjects with active AS despite current or previous NSAID,
DMARD and/or anti-TNF therapy.

Primary: To demonstrate the efficacy of each secukinumab regimen 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 TNFα
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 i.v. loading doses of 10 mg/kg at baseline, week 2 and 4.
Screening period of max. 4 weeks. Treatment period approx. 2 years.
Evaluation of efficacy at week 16. Patients on placebo, who do not show
improvement, will be switched at week 16 to secukinumab (randomized allocation
of dose). Patients who have shown a reaction, will continue placebo treatment
until week 24 and will be switched at that time point.
*Unblinded* local pharmacist.
Independent DSMB.
An interim analysis will be performed after all subjects have completed the
Week 52 visit.
Approx. 350 patients.
After study ends, possibility to enter an follow-up study.

Treatment with Secukinumab or placebo.

Risk: Adverse effects of study medication.
Burden: Study duration approx. 2 years. Approx. 30 visits: every 4 weeks (1st 4
visits 1-2 weeks apart). Fasting 7x. Duration 2-3 h.
3x i.v. infusion study medication (loading doses, 150 ml in 30 min),
subsequently s.c. injections every 4 weeks.
Physical examination 1st year every visit, 2nd year every 2nd visit.
Blood tests 1st 6 months every visit, thereafter every 2nd visit, 5-15
ml/occasion.
Optional pharmacogenetic/-genomics blood test (10 ml).
Pregnancy test (if relevant) every 4-12 weeks.
ECG 5x.
TBC skin test 1x.
Chest X ray 1x.
X rays spine: 2x.
DEXA scan 3x.
MRI scan (subset of patients) 3x.
Visual analogue scales disease activity and pain, ASQoL, BASFI, BASDAI, EQ-5D,
FACIT-Fatigue, SF-36, WPAI-GH. Per occasion 3-7 questionnaires (plus 2x 1 VAS).
1st 6 months every 4-8 weeks, thereafter end of year 1 and 2.