A randomized, double-blind, placebo-controlled, phase III multicenter study of subcutaneous secukinumab (150 mg) with and without a subcutaneous loading regimen to assess efficacy, safety, and tolerability 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.
lnterleukin-17 antagonism by secukinumab represents a novel approach to
interferewith ttie chronic inflammatory process. Notably secukinumab showed
good efficacy in patients with AS. This is based upon a 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 of secukinumab given as s.c. injections (prefilled syringes) 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.
Secondary (key only): ASAS40 week 16 response in the subgroup and whole study
population. Safety and tolerability.

Multicenter randomized double-blind phase Ill parallel-group placebo-controlled
study.
Randomisation (1 :1:1) to:

- Secukinumab 150 mg s.c. injections every 4 weeks with loading dose of one
injection every week during the first month
- Secukinumab 150 mg s.c. injections every 4 weeks without loading dose
(patient receives placebo during visit week 1, 2 and 3)
- Placebo until week 16, secukinimab 150 mg s.c. every 4 weeks after week 16

108 patients per treatment group.
Screening period of max. 10 weeks. Treatment period approx. 2 years. Follow-up
period 12 weeks.
Evaluation of efficacy at week 16. Patients on placebo will be switched at week
16 to secukinumab

Deblinding after interiim analysis week 52.

Treatment: Secukinumab or placebo.

Risk: Adverse effects of study medication.
Burden: Study duration appr. 2 years 23 site visits or 32 if patients cannot
inject themselves in year 2.
Year 1, visit every 4 weeks and during the first month weekly.
Year 2, visits every 12 weeks, every 4 weeks if injection takes place in the
hospital.
Fasting 9x
29 s.c. injections every 4 weeks (1st month weekly)
Bloodtest 19 times, 5-30 ml each time
Optional pharmacogenetic / genomics blood test (10 ml)
ECG at screening, after 16, 52, 76 and 104 weeks
Physical examination 23 times
Chest XRay 2 time
TBC skin test: 1 time
Visual analogue scales: Diseases activity, pain, BASFI, BASDAI, EQ-5D,
FACJT-Fatigue, SF-36, WPAI-GH; Per visit 3-7
questionnaires (plus 2x 1 VAS): Once every 1-3 months.