A randomised, double-blind, placebo-controlled,
multicentre prospective dose-finding Phase II/III study
with atacicept given subcutaneously to subjects having
recently experienced a flare of systemic lupus
erythematosus (SLE)

SLE is a chronic, usually life-long, potentially fatal autoimmune disease
characterised by
unpredictable exacerbations and remissions with protean clinical
manifestations. In SLE there
is a predilection for clinical involvement of the joints, skin, kidney, brain,
serosa, lung, heart
and gastrointestinal tract. The presence of anti-double stranded DNA antibodies
is a hallmark
of this disease. Roles for BLyS and APRIL in SLE have been suggested by both
animal and
human studies.
The aetiology of SLE remains unknown. A genetic predisposition, sex hormones,
and
environmental factors likely contribute to the disordered immune response that
typifies the
disease.
The origin of autoantibody production in SLE is unclear, but a role has been
suggested for an antigen-driven process, which is characterised by a
disturbance of immune
regulation that results in B cell hyper-responsiveness and production of
autoantibodies and
immune complexes that cause chronic inflammation and multiple organ damage.
Subjects with SLE present specific signs and symptoms such as fatigue,
arthralgia, skin rashes
and headache as well as symptoms that reflect multiple organ involvement. Most
subjects
with SLE will present involvement of the skin or joints. A common presenting
complaint is a
photosensitive rash, often associated with alopecia. Arthralgia or frank
arthritis is also very
common. Subjects may present with fever accompanied by single-organ
involvement, such as
inflammatory serositis, glomerulonephritis, neuropsychiatric disturbance or
haematological
disorder (i.e. autoimmune haemolytic anaemia or thrombocytopenia).
There is a very high unmet medical need for novel therapies with improved
risk/benefit ratios that would specifically affect manifestations of SLE and
increase subjects*
overall quality of life. New therapeutic agents for SLE
therefore need to reduce the need for corticosteroids and immunosuppressive
agents, control
end organ damage, reduce mortality and improve quality of life while having
limited side
effects.
Treatment of SLE subjects with atacicept is expected to reduce B cell numbers
and by
consequence the level of anti-dsDNA antibodies, thereby ameliorating
progression of disease
and survival as seen in murine models.

PRIMAIRY
The primary objective of this trial is to evaluate the efficacy of atacicept
compared to placebo
in preventing new flares in subjects with SLE.

SECONDARY
Secondary objectives of the trial are:
• To evaluate the safety and tolerability profile of atacicept in treated
subjects with SLE,
• To confirm the optimal dose of atacicept for treatment of subjects with SLE,
• To gain further information on the effect of atacicept on relevant markers
specific to its
mechanism of action (MoA) and their correlation to disease activity/progression,
• To further characterise the pharmacokinetic (PK) and pharmacodynamic (PD)
profiles of
atacicept, and
• To identify genetic and genomic variations associated with drug response and
disease
activity/progression.

This Phase II/III trial will enrol subjects with SLE who satisfy at least 4 of
the 11 ACR
(American College of Rheumatology) criteria and have a disease history of at
least six
months. Eligible subjects must have active SLE with at least one BILAG A or B
score
(excluding a single B due to haematological values) at screening that requires
a change in the
dose of corticosteroids, and must have positive anti-nuclear antibodies at
screening.
The subject will enter the initial flare treatment period and will be treated
with
corticosteroids according to regimens defined in the protocol (prednisone doses
as presented
in the table in Section 6.2.1or equivalent doses of other corticosteroids as
per Appendix J).
BILAG will be assessed 10 weeks after the start of corticosteroid treatment. If
the subject
improves from BILAG A or B to BILAG C or D within a maximum period of 10 weeks
and
if his/her steroid dose remains stable at a level of 7.5 mg prednisone or
equivalent for the
2 weeks following observation of BILAG improvement, a further BILAG assessment
will be
performed. If this assessment shows no BILAG A or B scores, the subject will be
considered
eligible for randomisation. Subjects who do not satisfy all of these criteria
will be withdrawn
from the trial; those who experience new BILAG A or B flares during the initial
flare
treatment period will also be withdrawn.
At the end of this approximately 13-week period, following confirmation of
continued
eligibility for the trial, subjects will be randomised in a 1:1:1 ratio to
receive one of two dose
levels of atacicept or placebo, given by subcutaneous (SC) injection.
The treatment period will consist of an initial loading period of 4 weeks,
during which the
assigned dose of atacicept or placebo will be administered twice weekly (BIW),
followed by
a maintenance period of 48 weeks, during which the assigned dose (75 mg, 150 mg
or
placebo) will be administered once weekly (QW). Due to the recent safety issue
and protocol amendment 6 resulted in the termination of the 150 mg arm. The
patients that received 150 mg were unblinded and stopped the study treatment.
The remaining patients are receiving 75 mg or placebo.
Subjects will be assessed before dosing on Study Day 1 (SD 1, defined as the
day of first
Investigational Medicinal Product administration), and then at the beginning of
Weeks 2, 4,
8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52. Three Follow-up visits will
take place at
Weeks 56, 64, and 76 (4, 12 and 24 weeks after the last dose).
In a subset of subjects in selected centres, flow cytometric analyses of B cell
subsets, T cells
and NK cells 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 50 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 registered by the trial*s
central
randomisation service.
A BILAG assessment should be performed in case of any suspected flare. If a
BILAG A or
B flare is confirmed after a BILAG assessment, the assessments planned for Week
24 will be
performed. Subjects who experience post-randomisation flares can be treated
with additional
corticosteroids (at a maximum to dose levels described in Section 6.2.1),
NSAIDs and
topical treatment and remain in the trial, provided that post-randomisation
flare treatment is
completed within 12 weeks of its initiation. If after this post-randomisation
flare treatment
the patient cannot be brought back on the treatment regimens he/she was
receiving at
randomisation, the patient must discontinue trial medication and will undergo
the 3 followup
visits as described in Section 6.2.5.

Hiervoor verwijzen wij graag naar de study flowchart in het protocol, pagina
114/115 en pagina 58 van het protocol (dosage and administration).

In a clinical trial like this one, every risk or side effect cannot be
predicted. Each person*s reaction to an experimental drug may be different. You
may have a side effect or be at risk for symptoms, illnesses or complications
that could not be predicted by your trial doctor or the Sponsor of this trial.
If any side effects occur, you must inform your trial doctor immediately.
Atacicept produced few side effects when tested in small studies in healthy
male volunteers and in people with cancer, rheumatoid arthritis (RA) and SLE.
The maximum single dose tested by subcutaneous injection was 630 mg and by
intravenous injection 1260 mg.
Overall, approximately 800 subjects have received at least one dose of
atacicept with a maximum of 8.5 months in treatment duration in completed
clinical research trials (including subjects with systemic lupus erythematosus,
lupus nephritis, multiple sclerosis, rheumatoid arthritis, optic neuritis,
multiple myeloma, non-Hodgkin*s lymphoma and B cell chronic lymphocytic
leukemia).
Some patients treated with atacicept for systemic lupus erythemathous have
experienced redness and pain at the site of injection. These reactions were
mild or moderate.
Treatment with atacicept also leads to a decrease in the number of cells in the
immune system called B-cells and in the levels of antibodies (also called
immunoglobulins) in blood. Both of these effects are thought to be important in
contributing towards the way that atacicept may help treat certain diseases.
Because antibodies and B-cells are also important in helping your body to fight
infection, there is an increased risk of mild or moderate upper respiratory
tract infections with the treatment with atacicept.
Some side effects of atacicept were observed in atacicept-treated patients with
other disease and have, to date, not been observed to be related to atacicept
in patients with systemic lupus erythemathous. These are the following:
In patients with multiple sclerosis, atacicept treatment was shown to cause an
increase in multiple sclerosis disease activity. Multiple sclerosis is a
disease affecting the central nervous system, leading to damage of the outer
layer (called myelin) that surrounds nerve cells. This process is called
demyelination. Therefore you cannot participate in this trial if you have or
have had any demyelinating disease such as multiple sclerosis or optic
neuritis. Your study doctor will provide you with more information if needed

Data from previous trials also suggested that exposure to atacicept may
increase the risk of allergic angioedema (swelling of the lips, face, mouth or
throat, which occurs within minutes or hours, and may be associated with other
allergic reactions like urticaria). If you experience such a reaction or other
allergic reaction, you should stop injecting atacicept and seek medical
attention as soon as possible.

Potential risks
A potential risk is a side effect that has not been confirmed to be related to
Atacicept. If any of the side effects mentioned below occur, you must inform
your trial doctor immediately.
Two subjects included in this trial who were receiving the high dose of
atacicept (i.e 150 mg) have died of a serious infection of the lungs called
pneumonia. This high dose has been now discontinued (this means that no
patient will receive atacicept 150mg at this time anymore) However, it can not
be excluded that exposure to any dose of atacicept may increase your risk of
having a similar serious infection.
Because of the effect of atacicept on antibodies and B-cells, treatment with
atacicept may increase your risk of infection including vaccine preventable
infections.

If you experience any, even mild, symptoms of an infection such as fever,
cough, shortness of breath, nasal congestion, headache, muscle and joint aches,
diarrhoea, flu-like symptoms, vomiting or any other symptoms of an infection,
it is important that you contact your study doctor immediately and are treated
swiftly and appropriately. You should stop taking study medication until a
proper evaluation by your doctor is completed. Please see the section *Study
procedures and requirements* for advice on avoiding infections and for guidance
in case you are hospitalised during the study participation.

In a previous study of subjects with severe active lupus nephritis, which is an
inflammation of the kidneys leading to loss of protein in the urine, three of
the four patients that received atacicept in combination with another recently
started treatment consisting of MMF (also called Cellcept or mycophenolate
mofetil) and corticosteroids were found to have low levels of immunoglobulins.
Two of these patients developed a serious infection of the lungs called
pneumonia. If you participate in this study, your antibody levels will be
tested every two weeks for the first month and then every month. If your
levels of antibodies fall too low, your study doctor will be informed and you
will be withdrawn from the study. If you develop fever, cough, shortness of
breath, flu-symptoms or chest pain, you should call your study doctor as these
can be symptoms of pneumonia.
In addition, if you are currently taking a drug called Cellcept, MMF or
mycophenolate mofetil, please tell your study doctor. This drug is not
permitted during this trial.

Some serious allergic reactions may be related to atacicept. These may involve
dizziness, low blood pressure (loss of consciousness is possible in the case of
very low blood pressure), difficulty in breathing and swallowing, heart
palpitations, abdominal pain, and vomiting. Prompt medical care is needed since
serious allergic reactions may be potentially life-threatening. If you think
you are having an allergic reaction, you should get immediate medical attention.

Treatment with atacicept could increase the risk of vertigo, balance problems
or other ear disorders. This could make you feel dizzy and lose your balance.
If you develop such disorders, you should not drive or operate machinery.

Results of previous trials suggest that atacicept could increase the risk of
developing new disturbances to the rhythm of the heart. If you develop such
events, you should contact your study doctor or study centre staff as soon as
possible.

Because atacicept modifies the immune system, there is a possible risk of
inducing new autoimmune diseases or making existing disease worse. However,
this has not been observed in previous SLE trials to date.

In other previous trials, very rare adverse events of cancer were observed in
subjects treated with atacicept for rheumatoid arthritis, systemic lupus
erythematosus and multiple sclerosis. The possible immunosuppressive effect of
atacicept could increase the risk of tumors. However, to date, such a link
between atacicept and tumors has not been proven.

Since only a limited number of subjects have been treated with atacicept and
these subjects have been followed for a relatively short time, the long-term
side effects of taking atacicept are unknown.

Study procedures include two chest X ray exams and regular blood sampling; some
minor risks are associated with these procedures.
The standard chest X-ray will involve a small radiation exposure. The radiation
exposure is very low and is equal to that you would get from natural sources
(like the sun) in less than 2 weeks.
Blood will be taken at each of the 21 study visits. A number of laboratory
tests will be performed (depending upon the visit, tests will differ). The
amounts of blood collected are unlikely to cause you any harm spread out over
the period of the study. The needles used to draw blood may cause local pain,
bruising and swelling. Some patients may also experience light-headedness,
dizziness, occasional (but rare) fainting or local infection. For your safety,
your study doctor may want you to have blood tests more frequently than your
scheduled study visits. He/She will let you know if this becomes necessary.
ECG (a test to check your heart) and measurements of blood pressure, heart rate
and body temperature are safe and are unlikely to cause discomfort.
In a pharmaceutical study like this one, not every risk or side effect can be
predicted. Each person*s reaction to a test, drug, or procedure may be
different. You may have a side effect or be at risk for symptoms, illnesses
and/or complications that could not be predicted by the study doctor or the
makers of atacicept.