A Phase IIa Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of JNJ-38518168 in Subjects with Active Rheumatoid Arthritis Despite Methotrexate Therapy With Synovial Biopsy Substudy

JNJ-38518168 is a potent antagonist of the histamine H4 receptor (H4R) with a
Ki of 8.4 nM and greater than 25-fold selectivity over other histamine
receptors. It inhibited histamine-induced shape change of eosinophils,
chemotaxis of mast cells, and IL-6 production in mast cells. The compound
inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-*)
production in vivo. JNJ-38518168 reduced arthritic edema and joint damage in a
collagen-induced mouse model of arthritis. Based on these preclinical data,
JNJ-38518168 may provide benefit to subjects with rheumatoid arthritis.

Hypothesis
* It is hypothesized that the mean improvement in DAS28 (using CRP) scores from
baseline will be superior to placebo at Week 12 when JNJ-38518168 is
administered to patients with active
rheumatoid arthritis despite methotrexate therapy.

Primary Objective
* To assess the safety, tolerability, and efficacy (in terms of change in DAS28
[using C-Reactive
Protein (CRP)] from baseline) of JNJ-38518168 at a dose of 100 mg/day for up to
12 weeks
compared to placebo in subjects with active Rheumatoid Arthritis (RA) despite
methotrexate
(MTX) therapy.

Secondary Objective
* To assess the efficacy of JNJ-38518168 as measured by ACR 20, 50, 70, 90
response rates at Week 12 and other efficacy assessments.

Exploratory Objectives
* To assess the effect of JNJ-38518168 on various biomarkers detected in
synovial biopsy tissue and blood samples
* To characterize the population pharmacokinetics (PK) of JNJ-38518168 in
adults with active
rheumatoid arthritis despite methotrexate therapy

This is a multi-center, randomized, double-blind, placebo-controlled,
parallel-group study. Approximately 90 subjects will be assigned to one of two
treatment groups (JNJ-38518168 100 mg/day [n=60] or placebo [n=30]) and will
receive study medication for up to 12 weeks.
At any point during the study, the subject*s dose may be decreased to 50 mg
daily, if in the opinion of the Investigator the 100 mg dose of JNJ-38518168 is
not well tolerated.
There is a 4-week follow-up period after dosing is complete. A substudy in
detecting biomarkers in synovial biopsy tissue will be performed at selected
sites in approximately 18 subjects (JNJ-38518168 100 mg/day [n=12] or placebo
[n=6]).

A Data Monitoring Committee (DMC) composed of sponsor clinicians and
statisticians and/or other individuals not associated with the conduct of the
study will review study data for safety purposes on an ongoing basis. Interim
analyses of unblinded data will be performed and then reviewed by the DMC on
two occasions: safety data when approximately 20% of subjects complete Week 12,
and safety and efficacy data will occur when approximately 50% of subjects
complete Week 12.

DOSAGE AND ADMINISTRATION
Each subject will receive one of the following treatments:
* JNJ-38518168 100 mg once daily for 12 weeks
* Matching placebo capsules once daily for 12 weeks
Study drug will be provided in 50 mg overencapsulated tablets (capsules). All
subjects will start at a dose of 100 mg qd taken in the morning on an empty
stomach with water. The dose may be decreased to 50 mg qd, if the study
medication is not well tolerated. The trial Medical Monitor must be notified of
dose reductions. If a subject*s dose is decreased to 50 mg qd, it will remain
at that level until the end of the study.

All Protocol Subjects
Blood samples will be drawn in all subjects at the times specified in the Time
and Events Schedule for the following assessments:
* Measurement of biomarkers which may include but not be limited to
inflammatory markers, autoantibodies, synovium/cartilage/bone markers and other
categories of biomarkers potentially
involved in the development and the progression of rheumatoid arthritis or
related to the JNJ-
38518168 mechanism of action.
* Microarray and RT-PCR analysis of RNA


Synovial Biopsy Substudy Subjects:
The following assessments will be performed at selected sites in a subset of
approximately 18 subjects (JNJ-38518168 100 mg/day [n=12] or placebo [n=6]) at
the times specified in the Time and Events Schedule:

* Synovial tissue samples collected via biopsy performed during the arthroscopy
or ultrasoundguided biopsy of one or more of the inflamed joints.
* Synovial inflammation will be assessed via immunohistochemistry and digital
imaging
analysis.
* RNA and epigenomic profiles will be analyzed in synovial tissues using
microarray and other
technologies.


PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
Exploratory PK/PD modeling may be conducted to evaluate the relationship
between plasma
concentrations of JNJ-38518168 and efficacy scores such as DAS28, ACR response
rates, and biomarkers.

PHARMACOGENOMIC EVALUATIONS
An optional pharmacogenomic blood sample (10 mL) will be collected to allow for
pharmacogenomic research (where local regulations permit).

SAFETY EVALUATIONS
Adverse events and concomitant medications will be collected from the time of
informed consent signing until study termination. Clinical laboratory tests,
vital signs and 12-lead ECGs will be assessed throughout the study at time
points specified on the Time and Events Schedule.
At any time following randomization, if a subject has an ECG with QTcF > 480
msec but < 500 msec, there will be a mandatory dose reduction to 50 mg qd with
a repeat ECG one week later. In addition, study medication will be discontinued
if there is an increase in QTcF interval [QT interval corrected using formula
of Fridericia] to an absolute value > 500 msec or if there is a change of > 60
msec over the baseline interval (average of 3 ECGs at randomization) OR if
there is a sustained QTcF interval > 480 msec but < 500 msec upon repeat ECG
one week after dose reduction.