A randomized double blind-placebo controlled dose ranging study to evaluate the efficacy and safety of SAR153191 in patients with Ankylosing Spondylitis (AS)

Ankylosing Spondylitis (AS) is a chronic, progressive inflammatory disease
characterized by inflammatory back pain, due to sacroiliitis, spondylitis and
enthesitis that affects young men and women, commonly starting in the second
and third decades of life. Traditional therapies
for AS are nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying
antirheumatic drugs (DMARDs) and physical therapy. However the above mentioned
therapies have limited efficacy. In contrast, the anti-Tumor Necrosis Factor
(anti-TNF) agents have shown better clinical efficacy in short and intermediate
* term evaluations, but 30% to 40% of patients are still anti-TNF resistant
(patients with no improvement in pain or function) (1)(2)(3). Patients who do
not respond to anti-TNF may be less responsive to other biological treatments.
Despite the medical therapies some patients still require surgical intervention
after failure of other treatments modalities.
Interleukin-6 (IL-6) is an important cytokine for the pathogenesis of AS. It is
mostly secreted by mononuclear phagocytes and activated Th cells. Its function
is to maintain growth and differentiation of B cells and the production of
immunoglobulins. There is evidence that the inflammation in AS is at least
partly mediated by tumor necrosis factor-alpha and IL-6, as high levels of
these cytokines have been found in biopsy from sacroiliac joints of patients
with AS. Also high levels of circulating IL-6 have been found in several groups
of AS patients. However, no IL-6 mAb has been approved in this indication.

The purpose of this study is to determine if SAR153191 SC (subcutaneous)
injection once a week or every other week is safe and effective compared to
placebo (an inactive solution injection ) in reducing the recurrence and
symptoms of Ankylosing Spondylitis. This is a specific condition you have.

This is a multi-center, multinational study. The design is a double-blind,
randomized parallel group placebo-controlled, 12 weeks study treatment of up to
6 arms (5 active dose regimens) or placebo. Patients with active AS will be
randomized in a ratio 1:1:1:1:1:1 (SAR153191:
placebo) with screening hs-CRP (hs-CRP *1.5 mg/L or >1.5 mg/L) and region as
stratification factors.
Patients will receive one of the 5 SAR153191 dose regimens (SAR153191 weekly or
SAR153191 every other week alternating with placebo every other week) or
placebo weekly for 12 weeks of treatment.

SAR153191 the anti-human IL-6R* antibody is a fully human monoclonal antibody
which will be administered subcutaneous one a week. The following doses are
selected:
- Arm 1: 100 mg SAR153191 once a week;
- Arm 2: 150 mg SAR153191 once a week;
- Arm 3: 100 mg SAR153191 every other week, alternating with placebo every
other week;
- Arm 4: 150 mg SAR153191 every other week, alternating with placebo every
other week;
- Arm 5: 200 mg SAR153191 every other week, alternating with placebo every
other week;
- Arm 6: placebo once a week.

This study comprises of 3 periods:
* Screening period (approximately 2 weeks):
* Treatment period (12 weeks):
* Post-treatment follow-up period (approximately 6 weeks from last drug
injection):
If the patient fullfills the treatment period completely, he or she can
participate in an extension study with open label SAR153191. This study will
start after 12 weeks of treatment. And the follow-up period will be declined.

De patient visits the hospital for a minimum of 7 visits and a maximum of 9
visits during the study. The first visit is the screening visit, which is
followed by a randomization visit (Day 1), a visit at week 2, 4, 8, 12 and 18.
The patient can take the opportunity to be visited at home by a home nursing
service at week 6 and 10. This is arranged by the sponsor. If the patient is
more comfortable to visit the hospital, then this is not a problem. During
these (hospital) visits bloodsamples will be taken, an ECG will be made, a MRI
and X-rays will be performed and several questionnaires have to be completed.
Further at the beginning of the study it will be checked if the patient does
not have Tuberculosis and/or Hepatitis B of C.

Bloodsamples
During blood draws, the patient may have pain and/or bruising at the place on
the arm where blood is taken. Blood clots may form and infections may occur,
but these events are rare. The amount of blood to be drawn will be
approximately 250 mL over 20 weeks.

Study medication
Treatment with SAR153191 may increase the risk of infection including
tuberculosis (TB), due to the fact that the immune system may become weaker and
not able to fight infections as it should therefore causing bacteria, fungi, or
viruses to spread throughout thebody. It is possible that the body may develop
antibodies (proteins that your body makes when exposed to foreign substances)
to this new drug.
The patient may suffer from bruises, pain or discomfort at injection or
puncture sites.

ECG, MRI and X-ray
There might only be a little discomfort, but not risk, when the
electrocardiogram electrodes are placed on the skin and the recording of the
electrocardiogram.
During the MRI the patient need not to move or change his/her position; and
this may be uncomfortable due to the AS.
Radiation exposure from an X-ray of the spine is equivalent to the amount of
radiation exposure one experiences from 6 months of natural sunlight. Radiation
exposure from a Chest X-ray is equivalent to the amount of radiation exposure
from 10 days of natural sunlight.

Pregnancy
If the patient has childbearing potential, she must either have been surgically
sterilised (tuballigation or hysterectomy) at least one month prior to study
entry or use an IUD (intrauterine device) combined with diaphragm, condom or
spermicide, or use an oral contraceptive (the pill) together with a barrier
method, in any case she must have a negative pregnancy test at the baseline
visit. and every 4 weeks during the study.