A randomised, double-blind, placebo-controlled, multicentre, Phase II dose-finding study of atacicept given subcutaneously in subjects with rheumatoid arthritis and inadequate response to TNFa antagonist therapy

Rheumatoid arthritis is a chronic inflammatory disease of the joints of unknown
cause. Certain mechanisms that lead to joint inflammation are becoming better
understood and research in rheumatoid arthritis suggests that B cells play an
important role in the development of the inflamation activity in the joints.By
decreasing the B cel population could give a positive effect on the
inflamation, which could result in a decrease of the inflamation activity,
pain, swelling and destructios of the joints. Atacicept recombinant fusion
protein functions as an antagonist to -B-Lymphocyte Stimulator (BlyS) and A
Proliferation Inducing Ligand (APRIL), these takes care for the growing of the
B-cels in the bone marrow.

The goal of this research trial is to evaluate the efficacy, tolerability and
safety of atacicept in patients with active rheumatoid arthritis who have an
inadequate response to other treatment(s). In addition, the study will also
measure the effects of atacicept on some parameters in the blood, which reflect
disease activity. This trial will also look at possible effects of atacicept on
disease progression.

This randomised, double-blind, placebo-controlled, parallel-arm, multicentre,
prospective dose-finding trial will enrol at least 288 evaluable subjects with
rheumatoid factor-positive active rheumatoid arthritis who have failed
treatment with a TNF* antagonist (defined below).
Screening will be performed within 28 days before the first dose. Following
provision of written informed consent and confirmation of eligibility for the
trial, subjects will be randomised in a 1:1:1:1 ratio to receive one of three
dose levels of atacicept or placebo, given by subcutaneous injection.
Subjects will be assessed before dosing on Study Day 1 (SD 1, defined as the
day of randomisation and first Investigational Product administration), and
then on Days 8 and 22 and at the beginning of Weeks 8, 12, 16, 20 and 26. A
final Follow-up visit will take place at Week 38, 13 weeks after the last dose.
In a subset of subjects in selected Western European centres, flow cytometric
analyses of B cell subsets, T cells, NK cells and monocytes in peripheral blood
will be performed to characterise atacicept*s effects on these cell
populations. Pharmacokinetic sampling will also be performed at additional time
points for this subset, which will consist of 24 subjects from each treatment
group, including placebo. All subjects in the participating centres will
provide consent for these procedures; the subjects who will be part of the
subset will be selected by the trial*s central randomisation service.

Treatment will consist of a loading period during the first 4 weeks, during
which the assigned dose will be administered twice weekly (BIW) followed by a
maintenance period over the next 21 weeks, during which the assigned dose will
be administered once weekly (QW). Thus:
* Group 1: atacicept 25 mg BIW for 4 weeks, followed by atacicept 25 mg QW for
21 weeks.
* Group 2: atacicept 75 mg BIW for 4 weeks, followed by atacicept 75 mg QW for
21 weeks.
* Group 3: atacicept 150 mg BIW for 4 weeks, followed by atacicept 150 mg QW
for 21 weeks.
* Group 4: placebo BIW for 4 weeks, followed by placebo QW for 21 weeks

The duration of the study is as follow: screening period of 1 to 4 weeks prior
to study medication; treatment period of 25 weeks, follow up period of 13
weeks. In total 10 visits.
The screeening visit can take more then 2 hours, but after this each visit
will not take more then 1 hour. During the scrrening visit the demochrafic
data, full medical history and rheumatology history, medication history and
data regarding opperration pracedures will be collected, a x-ray of the thorax
will be performed
Blood samplings and urine analysis will take place on 10 occasions at the
following visits: screening, SD1, SD8, SD 22, weeks 8, 12, 16, 20, 26 and at
the final follow-up visit. In a subset of subjects in selected Western European
centres, flow cytometric analyses of B cell subsets, T cells, NK cells and
monocytes in peripheral blood will be performed to characterise atacicept*s
effects on these cell populations
Pharmacokinetic sampling will also be performed at additional time points for
this subset, which will consist of 24 subjects from each treatment group,
including placebo. All subjects in the participating centres will provide
consent for these procedures; the subjects who will be part of the subset will
be selected by the trial*s central randomisation service.Standard ECG will be
performed at screening, SD1, SD8, SD22, weeks 8, 12, 16, 20, 26 and final
follow up visit.
Disease activity assessments at screening, SD1, SD8, SD22, weeks 8, 12, 16, 20,
26 and at the final follow up visit
Quality of Life questionnaire (SF-36) on SD1 and week 26.
Physical examination will take place at screening, SD1, final follow- up visit
and as required by routine clinical care
Female subjects will have an urine pregnancy test at screening, SD1, SD22,
weeks 8, 12, 16, 20, 26 and at the final follow-up visit.
Collection of information on adverse events, local tolerability, concomitant
medication and procedures will take place at every visit.
Optional Pharmacogenomics samplings will take place on SD1 and at week 26, for
this a seperate patient information and consent form is available.
In order to reduce the risks the standard procedures which will be used for the
used assessments, will be done as clean and sterile as possible.
Possible side effects of the study medication are written on page 17,18 and 19
of the protocol. The main adverse effects reported included headaches,
respiratory tract infections with cold/flu symptoms, sore throat and
gastrointestinal disorders such as nausea, vomiting and diarrhea, but a causal
relationship between atacicept and these symptoms and illnesses has not been
established. There have been transient reactions at the injection site (redness
and swelling).As with other medications, people treated with atacicept may be
at risk of developing allergic reactions or anaphylaxis. Symptoms of an
allergic reaction generally include overall body itching, hives, skin flushing,
or rash. Anaphylaxis is a more serious allergic reaction that may involve
dizziness, low blood pressure (loss of consciousness is possible in the case of
very low blood pressure), difficulty breathing and swallowing, palpitations,
abdominal pain and vomiting.