A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL
GROUP, MULTI-CENTRE STUDY TO INVESTIGATE THE SAFETY AND
EFFICACY OF CP-690,550 FOR INDUCTION THERAPY IN SUBJECTS WITH
MODERATE TO SEVERE CROHN'S DISEASE

Tofacitinib is being developed for the treatment of adult patients with
moderate-to-severe Crohn*s disease. Crohn*s disease is a chronic relapsing,
transmural inflammatory disease that can affect the entire gastrointestinal
tract and is most commonly located in the ileum and colon (40%) or just
involves the small bowel (30%) or the colon (25%). Although the cause remains
unknown, the most likely pathogenesis of Crohn*s disease is defective
immunoregulation in genetically susceptible patients, leading to an
upregulation of macrophages and Th1 lymphocytes and the production of an excess
of cytokines, interleukins and chemokines, all of which can lead to enhanced
inflammation, impaired wound healing and tissue damage. Increasing evidence
suggests that upregulation of some cytokines that use the common gamma-chain in
their signal transduction pathways may play a role in the pathogenesis of
inflammatory bowel disease. At present, no current pharmacological therapy
provides a cure for Crohn*s disease and the treatment goal is to induce and
then maintain remission. Despite available treatment options, there is still a
large unmet medical need with many patients failing to achieve clinical
remission or experiencing apparent loss of initial efficacy with continued use.
Surgery also is not curative and often followed by disease recurrence. Thus,
there is need for a novel therapy that will surpass the efficacy of currently
used agents, but will have less toxicity and a more convenient route of
administration. tofacitinib is a potent, selective inhibitor of the JAK family
of kinases, thereby blocking signaling through the common gamma
chain-containing receptors for several cytokines that are integral to
lymphocyte activation, proliferation and function: inhibition of this signaling
pathway by tofacitinib may thus result in modulation of multiple aspects of the
immune response and thereby offers a novel therapeutic approach for the
treatment of Crohn*s disease. The primary objective of this study is to
characterize the dose-response relationship of tofacitinib in inducing clinical
remission in subjects with moderate to severe Crohn*s disease and to select
effective doses. Please see chapter 1 of the protocol (introduction) for more
details.

Primary objective:
The primary objective of the study is to evaluate the dose-response of
tofacitinib in inducing clinical remission in subjects with moderate to severe
Crohn*s disease and to select effective doses.

Secondary objectives:
-To evaluate the safety and tolerability of tofacitinib induction therapy in
subjects with moderate to severe Crohn*s disease.
-To evaluate the dose-response of tofacitinib in inducing clinical response in
subjects with moderate to severe Crohn*s disease.
-To characterize the pharmacokinetics of tofacitinib in subjects with
moderate to severe Crohn*s disease. -To evaluate the effect of tofacitinib on
quality of life in subjects with moderate to severe Crohn*s disease.
-To evaluate the effect of tofacitinib on CRP and fecal calprotectin.

This is a phase 2b, randomized, double-blind, placebo controlled, parallel
group, doseranging, multi-centre study in subjects with moderate to severe
active Crohn*s disease. This study consists of a screening period of 1 to 3
week duration and an 8-week double-blind treatment period, followed by a 4-week
safety follow-up for subjects who do not continue in a 26-week maintenance
study (Study A3921084). Approximately 275 subjects will be enrolled into the
study. After the screening period, subjects who meet inclusion and exclusion
criteria at the baseline visit will be randomly assigned to receive one of
three treatments (tofacitinib 5 mg BID, 10 mg BID or placebo BID) with an
allocation ratio of 1:1:1. Subjects will be stratified by whether or not they
have previous exposure to anti-TNFα therapy. Subjects will receive double-blind
treatment for 8 weeks. Subjects who complete the 8-week double-blind treatment
and achieve clinical response-100 (defined by a decrease in CDAI score of at
least 100 points from baseline) and/or are in clinical remission (CDAI < 150)
are eligible to enter a 26-week maintenance study (Study A3921084). Subjects
who withdraw early from the study and discontinue from the double-blind phase
early will be asked to complete EOT/Early Withdrawal study procedures at Week
8. These early withdrawal subjects, along with subjects who complete the
double-blind treatment period but are not eligible or are not willing to
participate in Study A3921084, will be asked to complete EOS/Follow-up visit at
Week 12, approximately 4 weeks after the last dose of study drug. Subject to
IRB/EC approval, this trial will include an additional optional research
component involving collection of biological samples for de-identified genetic
analysis. The Molecular Profiling Supplement to this protocol provides a
description of this additional research. Subjects may participate in the
pharmacogenomics component of the research after signing an additional informed
consent form.

Subjects will be randomly assigned to receive one of three treatments
(tofacitinib 5 mg BID, 10 mg BID or placebo BID) with an allocation ratio of
1:1:1. Subjects will be stratified by whether or not they have previous
exposure to anti-TNFα therapy. Subjects will receive double-blind treatment for
8 weeks. The study drug and placebo are in the form of tablets and patients
will be asked to orally take 2 tablets twice a day. Please see section E4 of
this ABR form for the procedures to which the subjects will be subjected.

The unmet medical need in patients with Crohn*s disease, expected efficacy of
tofacitinib in this indication and the safety profile of the compound which has
emerged from the phase 2/3 programs in RA and other indications, imply that
tofacitinib has a novel anti-inflammatory mechanism of action which is
anticipated to be possibly effective in treating Crohn*s disease. The benefits
to the subjects participating in this study will be a potential control of the
disease activity by improving symptoms (stool frequency, abdominal pain) and
general well-being. All subjects may also benefit from gaining knowledge about
their health status through study tests and physician assessments, as well as
having close monitoring of their inflammatory bowel disease.

The risks associated with tofacitinib are similar to the risks associated with
the use of other immunosuppressive agents, including a potential increased risk
for infections. Decreases in white blood cell counts, particularly neutrophils,
and decreases in haemoglobin have been observed. These effects were usually
mild to moderate and returned to normal after discontinuation of therapy. In
previous studies with tofacitinib, increases in levels of LDL and HDL
cholesterol were also reported, with the ratios of total / HDL cholesterol
unchanged. The long-term implications of these changes for cardiovascular risk
are currently unknown. Also seen in previous studies were slight increases in
measured serum creatinine and serum transaminases. This effect generally
returned to normal after discontinuation of therapy. Infections, anemia and
neutropenia are all consistent with the pharmacology of tofacitinib as a potent
inhibitor of JAK3 with cross-over to JAK1 and moderate selectivity for JAK2.
Hypothetical safety risks that may be associated with the use of tofacitinib
include an increased risk of lymphoma and lymphoproliferative disorders,
malignancy and teratogenicity.

The available data on the potential and identified risks of tofacitinib are
thus considered to not preclude clinical studies in Crohn*s disease patients
and the risks are minimized through appropriate pre-enrolment screening and
close safety monitoring. Therefore, the overall risk-benefit assessment for
this study is considered to be favourable.