A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study to Evaluate Efficacy and Safety of Treatment with CNTO 136 Administered Intravenously in Subjects with Active Lupus Nephritis

Currently, determining appropriate treatment for the patient with LN is a
challenge, in part because LN is not a single pathophysiologic condition but
rather it represents a group of different classes of inflammatory kidney
disease, clinically and pathologically. The current International Society of
Nephrology/Renal Pathology Society (ISN/RPS) classification system of LN
includes 6 major clinicopathologic classes (Weening et al, 2004), with Class
III and IV disease considered more severe and having a poorer prognosis. LN
occurs in about 40% to 70% of SLE patients and accounts for substantial
morbidity and mortality (Cameron, 1999; Seligman et al, 2002). Some whose
disease is too advanced at the time of diagnosis or who fail therapy, will
progress to end stage renal disease, dialysis, and/or renal transplantation
(Cameron, 1999; Austin and Balow, 1999).

Approved therapies for active LN are lacking. Oral and parenteral
corticosteroids (eg, prednisone, methylprednisolone) are indicated to induce
remission of proteinuria in nephrotic syndrome due to SLE but no drug addresses
patients with LN that is non-nephrotic (< 3 gm protein/24 hr urine). A few
drugs are indicated for use in SLE, generally for milder, nonrenal
manifestations, or for the intralesional treatment of discoid LE. Progress in
developing new treatments for LN has been hampered by the great heterogeneity
of the patient population, limited prevalence of LN, and its variable disease
course (Boumpas et al, 2005).

Multiple lines of evidence implicate the cytokine IL-6 in the immunopathology
of LN, and studies in the NZB/W F1 murine lupus model have shown that IL-6
inhibition can ameliorate nephritis in this model. In the small open-label
lupus trial of the anti-IL-6 receptor antibody tocilizumab, some reductions in
hematuria or pyuria were observed, but altogether there were only 5 subjects
with renal disease (Illei et al, 2010). CNTO 136 is a high affinity human mAb
that inhibits the activity of human IL 6. Multiple doses of CNTO 136 of up to
10 mg/kg IV were reasonably well-tolerated in subjects with mild CLE and SLE.
This protocol is the first clinical trial to evaluate the potential therapeutic
benefit of CNTO 136 in subjects with active LN.

Primary Objective(s)
The primary objective is to evaluate the efficacy and safety of CNTO 136
administered intravenously in subjects with active, ISN/RPS Class III and IV LN.

Secondary Objectives
The secondary objectives are:
Evaluate the pharmacokinetics and immunogenicity of CNTO 136 following IV
administration in subjects with active ISN/RPS Class III and IV LN
Assess the pharmacodynamic effects of CNTO 136 IV in subjects with active
ISN/RPS Class III and IV LN

Exploratory Objectives
Identification of biomarkers that reflect response to CNTO 136 treatment, or LN
disease activity
Assess the patient-reported changes in symptoms, physical function, and
perception of health status

Hypothesis: The study is exploratory in nature and will generate hypotheses
for future testing. No formal hypothesis testing will be performed during this
study.

This is a randomized, double-blind, placebo-controlled, parallel group,
multicenter, proof of concept study of CNTO 136 in subjects with active LN
currently not on cyclophosphamide. Following an 8 week run-in period to
establish the stability of baseline renal parameters, approximately 24 subjects
will be randomly assigned to treatment, 20 subjects to CNTO 136 10 mg/kg IV and
4 subjects to placebo IV. Study treatments will be administered every 4 weeks
with the last dose at Week 24 for a treatment duration of 24 weeks. Subjects
will be followed through Week 40 for efficacy and safety.
The study will end when the last subject completes the Week 40 visit or, in the
event that the last subject randomized withdraws from the study early, the end
of study is defined as the last visit of the last subject participating in the
study.

A Data Review Committee (DRC) which includes clinical and statistical members
internal to Johnson & Johnson and independent of the study, will be formed.
Upon study team recommendation, the DRC will assess unblinded safety data and
make recommendations regarding the study. The confidentiality of any unblinded
information will be maintained until the study is terminated and the database
is locked.

When the clinical study is terminated and the database is locked, then all of
the study data are unblinded and a clinical study report is written describing
the results and analyses.

Prior to the first infusion, eligible subjects will be randomly assigned in a
5:1 ratio to 1 of 2 treatment groups as follows:

Group 1: CNTO 136 10 mg/kg IV, Weeks 0, 4, 8, 12, 16, 20, 24
Group 2: Placebo infusion, IV, Weeks 0, 4, 8, 12, 16, 20, 24

Subjects will be followed for efficacy and safety through Week 40.

The following riks related to the medication and related to participation, are
referred to in the information for the patient:

The possible discomforts, side effects and risks as the result of the sirukumab
treatment are not all known. All drugs can cause side effects.
Most side effects are mild to moderate in nature, but some of them can be
serious and /or require treatment or additional tests.

To date not many people have been treated with sirukumab. The most common side
effects that have been reported were headache, cold and sore throat, but
unknown severe side effects may also occur.

Tell your doctors or dentist that you are taking part or have taken part in a
study with an anti-IL-6 agent (sirukumab). This is important if you have to
undergo an operation, dental surgery, or treatment for another medical
condition.
Tell your study doctor straight away if you have one of the following symptoms
or conditions:
- a persistent cough, shortness of breath, fever, night sweats, loss of weight,
signs of an infection, an infection that keeps coming back, if you anyone
from your family has been in contact with someone who is suffering from
tuberculosis.
- If you have had cancer
- If you have liver problems, including hepatitis B and C

Infections

Sirukumab is a drug that can change the ability of your body combat infections.
People who have been given sirukumab or comparable medicines, have reported
infections, including severe infections that required admission to hospital.
Sirukumab can prevent a fever developing when you have an infection and
therefore may hide a sign that you may have one. You could get infections more
often if you use this drug.

Blood
Sirukumab can reduce the number of blood cells that help the body to combat
infections and stop bleeding. Sirukumab can increase different types of
cholesterol and can have an effect on your liver.

The study doctor will check with blood tests whether there are any abnormal
results for:
• blood cells (help the body to combat infections and stop episodes of
bleeding)
• liver tests
• various types of cholesterol and fats

Allergic reactions
• Allergic reactions can be caused by any medicine, also by the study
medicine. Some may be severe. The following signs can be signs of an allergic
reaction: shivers, rash or hives, nausea, hot flushes, light-headedness,
irregular heartbeat, tightness of the chest or wheezing, difficulty breathing
or swallowing, low blood pressure, swelling in face, lips, tongue and/or
throat.

Severe allergic reactions, which are called anaphylaxis, have been reported
with medicines such as sirukumab and can be life-threatening. If you get a
severe reaction, you will not be given any more study medicine and you could be
treated with antihistamines (these are medicines for allergy) or paracetamol
(for pain and fever).
If you have an allergic reaction, it is possible that you can never use this
sort of medicine again in the future.


Reactions to the infusion
Your body can react during or after the infusion into your vein. This is called
an infusion reaction. These reactions are usually mild. They are managed by
slowing the infusion or by giving you medicine.
Serious allergic reactions called anaphylaxis have been reported with drugs
like sirukumab. These can be life threatening. Your doctor will treat you if
this should happen.

Vaccines
You are not allowed to have a *live* vaccine (for example FluMist*, BCG,
chicken pox) during this study or for 4 months after the last study injection.
You could become ill from this type of vaccine if you are being given
sirukumab. Other types of vaccines, such as against tetanus or flu, are
allowed. If you are given a vaccination with a live vaccine during this study,
you must report it to the study doctor.
It is possible that you will no longer be able to receive any study medicine
thereafter.

Additional known risks of a comparable medicine (tocilizumab)
In people who have used a comparable medicine, the following side effects have
been reported: gastrointestinal perforations (tears in the stomach or
intestines), cancer and a particular type of nervous system condition that can
give rise to symptoms such as changes in the visual acuity, weakness, deaf
feeling or tingling. Medicines such as this reduce the activity of the immune
system. So the risk of particular types of cancer can increase if the immune
system cannot deal with them.

Other risks
You may also be at risk of other discomforts or risks in connection this study,
which are not yet known. Your study doctor and personnel will ask you at each
visit about the side effects that you can have.
If you have side effects or problems, report them immediately to your study
doctor.

Discomfort of the procedures: the infusion and taking blood.
You could experience discomfort when the needle is pricked in your vein to
administer study medicine or to take blood. (Could be troubled by having a
small bruise, a change of colour, swelling or a scar where the vein was
entered, or faint).

The quantity of blood that is taken in the course of the whole study is less
than the quantity of blood that you would give to a blood bank as a blood
donor.

Other procedures such as measuring the blood pressure and an ECG (heart trace)
do not normally involve you in a risk.