A 54-week, phase II, multi-center, open-label extension study to evaluate the efficacy, safety and tolerability of ACZ885 (anti-interleukin-1beta monoclonal antibody) in patients with rheumatoid arthritis

In this trial the medication ACZ885 is being investigated. ACZ885 is possibly a
new medication that is developed to treat rheumatoïd arthritis, and other
inflammatory diseases. The agent has not been registered yet as medicine and
does not have a name yet.
ACZ885 is a protein that binds to one of the most important inflammatory
proteins which control the rheumatoïd process, interleukin-1* (IL-1*). In the
rheumatoïd inflammatory process IL-1* binds to cells in the joints which are
then stimulated to control the inflammatory process. This process leads to
pain, swelling and limitations of the joints, and eventually also damage.
ACZ885 blocks the action of IL-1* by binding to it. Hereby the inflammatory
process gets the chance to rest, and could decrease the complaints of
rheumatoïd arthritis.

ACZ885 has been investigated in healthy volunteers, patients with asthma,
patients with rheumatoïd arthritis and patients with rare defence system such
as Muckle Wells-Syndrome. Until now 133 have been treated with ACZ885 (18
healthy volunteers and 115 patients).

To assess the long-term safety and tolerability (and in particular the
infection occurrence) of
ACZ885 in patients with rheumatoid arthritis (RA) who participated in the core
CACZ885A2204,
CACZ885A2206, or CACZ885A2207 studies.

This will be a multicenter, open-label, non-randomized trial without comparator
which will extend active treatment by 54 weeks to those patients who completed
the core CACZ885A2204, CACZ885A2206, or CACZ885A2207 study in order to collect
long-term safety data.
Upon signing the informed consent, the following groups of patients will be
allowed to enter the
extension study:
* Patients who were exposed to the 26-week active treatment arm, ACZ885 (+
metothrexate)
600 mg intravenous (i.v.) loading dose on Day 1 and Day 15 followed by
additional i.v. infusions of 600 mg monthly, in the core CACZ885A2204 study and
completed the study up to
visit 18 (Week 30) without serious or severe drug-related adverse effects.
* Patients who were exposed to placebo (+ metothrexate) in the core
CACZ885A2204 study
and completed the study up to visit 18 (Week 30) without serious or severe
drug-related
adverse effects.
* Patients who were exposed to one of the four 6-week active treatment arms,
ACZ885
10 mg/kg s.c., ACZ885 5 mg/kg i.v., ACZ885 2 mg/kg s.c., or ACZ885 1 mg/kg i.v.
administered as two single doses on Day 1 and Day 15, in the core CACZ885A2206
study and
completed the study up to visit 7 (Day 43 / Week 6) without serious or severe
drug-related
adverse effects.
* Patients who were exposed to the 12-week active treatment arm, ACZ885 600 mg
i.v. loading
dose on Day 1 and Day 15 followed by one additional i.v. infusion of 600 mg at
Day 43, in the
core CACZ885A2207 study and completed the study up to visit 7 (Day 85 / Week
12) without
serious or severe drug-related adverse effects.
* Patients who were exposed to placebo in the core CACZ885A2207 study and
completed the
study up to visit 7 (Day 85 / Week 12) without serious or severe drug-related
adverse effects.
The assessments performed at the last visit of the core study (as specified
above) will correspond to the assessment of the first visit of the extension
study, i.e. baseline visit (see Figure 1). Therefore, the assessments should
not be performed twice (however, the assessments will be recorded twice, i.e. in
both study Case Report Forms). The baseline evaluation period before first
dosing (from Day -7 to Day -1) will be used to assess eligibility. Informed
consent for this study must be obtained prior to conducting any study related
activities for patients entering from one of the core studies.
All patients will be administered 600 mg ACZ885 as an i.v. infusion, regardless
of their treatment arm
in the core study. ACZ885 dosing will occur on Day 1 and from then on every 6
weeks (± 5 days) at
the study site.
The 54-week treatment period will be followed by a follow-up period of 3 months
and a study
completion visit.
Safety, tolerability, efficacy, PK, and PD will be assessed every 6 weeks at
each clinical visit.
Immunogenicity will be followed up every 3 months.

All patients will be administered 600 mg ACZ885 as an i.v. infusion, regardless
of their treatment arm
in the core study. ACZ885 dosing will occur on Day 1 and from then on every 6
weeks (± 5 days) at
the study site.

Participation in a trial with a new medication brings a certain risk and
discomfort. Until now 133 men and women have been treated with ACZ885. Most
persons have received ACZ885 via an infusion. Thirty-one persons have received
ACZ885 as subcutaneous injection.

No serious adverse events have occurred yet which led to discontinuation of the
trial, or the use of the investigational product after the first dose. One
patient stopped by himself, due to dizziness, nausea and headache after the
first dose. 6 adverse events have been reported which have led to a
hospitalization: a spontaneous abortion after 8 weeks pregnancy of a healthy
volunteer, a broken left thigh due to a fall with the bike by a patient with
rheumatoid arthritis, developing of pain on the chest (possibly angina
pectoris) by a patient with rheumatoid arthritis and 3 infections, amongst
which erysipelas (infection of the skin), possibly a lung infection and
bronchitis, in patients with rheumatoid arthritis. All three infections
responded well to a treatment of antibiotics. Whether the adverse events are
correlated with ACZ885 is not clear. In none of the earlier trials,
medication-related changes occurred in blood pressure, pulse, ECG and
laboratory values used to determine the safety.
The preliminary conclusion is the ACZ885 is well tolerated and the there are no
data which have led to worry about the safety of ACZ885.