A randomized, double-blind, placebo-controlled multicenter study of secukinumab 150 mg in patients with active non-radiographic axial spondyloarthritis to evaluate the safety, tolerability and efficacy up to 2 years, followed by an optimal phase of either 150 mg or 300 mg randomized dose escalation for up to another 2 years

The well-known ankylosing spondylitis is part of axial spodyloartritis, The
form of spondyloartritis that shows no damage on X-Ray is called non-axial
radiographic spondylartritis. These patients have the same symptoms and risk
factors that are characteristic of axial spondylartritis. Spondyloartritis 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.
Secukinumab is administered as s.c. injections 150 mg (in pre-filled syringes)
versus placebo in patients with active axial non-radiographic spondylarthritis.
It is the intention that the patients administer the injections themselves in
the second year if possible.
The core phase is followed by an optional 16-week extension phase that lasts
for up to 2 years, but stops when the last patient has completed the first 16
weeks of this phase. During this phase it will be investigated whether a dose
increase from 150 mg to 300 mg secukinumab has more benefits for patients
compared to 150 mg. Long term efficacy, safety and tolerability of the 300 mg
dose are investigated.

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 40 response.
Secondary (key only): ASAS responses 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 , if inadequate response at week 20 secukinimab 150 mg s.c. every 4
weeks. After a year secukinumab for all placebo patients.
155 patients per treatment group. 555 patients in total.

Screening period of max. 10 weeks. Treatment period approx. 2 years. Follow-up
period 8 weeks.
Evaluation of efficacy at week 16. Patients on placebo can be switched at week
20 to secukinumab if inadequate response.
Deblinding after interiim analysis week 52.

In week 104, patients can continue with an optional, randomized extension
treatment with a higher dose. Patients will be assessed for their ASA20
response at week 104. Secukinumab 150 mg responders at week 104 are
blind-blinded in one of the following groups:
4. Secukinumab 150 mg / placebo, every 4 weeks
5. 2 injections of Secukinumab 150 mg every 4 weeks

Patients who have not fully responded to Secukinumab at week 104 will receive a
higher dose in an open-label manner:
6. 2 injections of 150 mg Secukinumab every 4 weeks (open label)

Treatment: Secukinumab or placebo.

Risk: Adverse effects of study medication.
Burden: Study duration appr. 2 years. 24 site visits or 33 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. Average duration visit 2 hr.
29 s.c. injections every 4 weeks (1st month weekly)
Blood test 19 times, 5-30 ml each time
Optional pharmacogenetic-genomics blood test (1 0 ml)
Optional biomarkers blood test 5x (1 ml)
ECG at screening and at week 16, 52, 76 and 104
Physical examination ca 23 times
Chest X-Ray: 2x
X-Ray cervical, thoracal and lumbal spine: 2x
X-Ray Sacro iliiacal joint: 2x
TBC skin test: 1x
Visual analogue scales: Diseases 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.

Extension phase (maximum burden)
Duration: maximum 2 years and 11 visits, on average 2 hours per visit
26 s.c. injections every 4 weeks
Physical examination: 9x
Questionnaires: 5x
Blood collection for lab determinations: 9x
Pregnancy test (if applicable): 9x