A Phase 3, Multicenter Study to Evaluate the Long-Term Safety and Efficacy of Baricitinib in Patients with Rheumatoid Arthritis.

Baricitinib (LY3009104) is an oral Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2)
selective inhibitor representing a potentially effective therapy for treatment
of patients with moderately to severely active rheumatoid arthritis (RA). The
rationale for the current study is to evaluate the safety profiles and
durability of effect of 2 mg and 4 mg baricitinib doses when administered once
daily (QD) over an extended time period to patients with RA who have completed
a previous Phase 2 or Phase 3 study of baricitinib. The safety and
tolerability data from this study are intended to inform the current
understanding of the benefit-risk relationship for baricitinib in patients with
RA.

The primary objective of the study is to evaluate the long-term safety and
tolerability of baricitinib in patients who have completed a previous
baricitinib RA study. Safety and tolerability assessments will include:
* Treatment-emergent adverse events (TEAEs), adverse events of special interest
(AESIs), and serious adverse events (SAEs)
* Temporary investigational product interruptions and permanent investigational
product discontinuations
* Vital signs and laboratory evaluations (including chemistry and hematology)

The secondary objective(s) of the study are:
To evaluate in patients initially randomized to receive baricitinib in the
originating study, the effect of long-term administration of baricitinib as
assessed by:
* Proportion of patients who maintain an improvement of 20, 50, or 70 percent,
respectively, in the American College of Rheumatology criteria (ACR20, ACR50
and ACR70) from Month 6 (of the originating study) through Months 12, 24,
36, 48, and 54 of baricitinib treatment
* Proportion of patients who maintain a Disease Activity Score modified to
include the 28 diathrodial joint count (DAS28)-high sensitivity C-reactive
protein (hsCRP)/DAS28 erythrocyte sedimentation rate (ESR)*3.2 and Clinical
Disease Activity Index (CDAI) *10, and Health Assessment Questionnaire
Disability Index (HAQ-DI) improvement *0.22 and *0.3 from Month 6 (of the
originating study) through Months 12, 24, 36, 48, and 54 of baricitinib
treatment
* Change from baseline of originating study to Month 12 (Study JADX), Month 24
(Studies JADX, JADV and JADZ), Month 36 (Studies JADA, JADV, and JADZ), and
Month 48 (Study JADA) in structural joint damage as measured by modified Total
Sharp Score (mTSS) [van der Heijde method])
* Proportion of patients with mTSS change *0 from baseline of originating study
to Month 12 (Study JADX), Month 24 (Studies JADX, JADV, and JADZ), Month 36
(Studies JADA, JADV, and JADZ), and Month 48 (Study JADA)
* Change from baseline of originating study to Month 12 (Study JADX), Month 24
(Studies JADX, JADV and JADZ), Month 36 (Studies JADA, JADV, and JADZ), and
Month 48 (Study JADA) in joint space narrowing and bone erosion score
* Change from baseline of originating study in duration of morning stiffness
at 12, 24, 36, 48, and 54 months of baricitinib treatment
* Change from baseline of originating study through Month 24 in European
Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) scores
* Evaluation of healthcare resource utilization through Month 24

Similar analyses will be conducted on patients who initiated treatment with
baricitinib as rescue therapy at some time during the originating study.

The exploratory objective(s) of the study are:
* To determine if treatment with baricitinib 2 mg QD maintains the low disease
activity level or remission achieved with the 4 mg QD dose (ie, step-down
dosing) on the following outcomes:
o Proportion of patients who maintain a CDAI score of *10 (or *2.8 if from
Study JADZ) after 3 months of treatment with baricitinib 2 mg QD and with
patients continuing treatment with the 4 mg QD dose
o Time to relapse (where relapse is defined as a CDAI score >10 or >2.8 if from
Study JADZ) after randomization to the baricitinib 2 mg and 4 mg QD doses
* To describe the clinical course of patients initiating baricitinib at the
time of enrollment in Study JADY as assessed by DAS28-hsCRP, DAS28-ESR, and
CDAI at 3,6, 12, 18, and 24 months of baricitinib treatment by initial
treatment allocation in the originating study.
o From placebo in Studies JADW or JADX to baricitinib in Study JADY
o From methotrexate (MTX) in Study JADZ to baricitinib in Study JADY
o From adalimumab in Study JADV to baricitinib in Study JADY
* To describe the clinical course of patients switching from MTX + baricitinib
in Study JADZ to baricitinib monotherapy in Study JADY as assessed by
DAS28-hsCRP, DAS28-ESR, and CDAI at 3, 6, 12, 18 and 24 months of baricitinib
monotherapy

Study I4V-MC-JADY (JADY) is a Phase 3, multicenter, long term extension study
evaluating the safety and efficacy of baricitinib (2 mg QD and 4 mg QD) in
patients with rheumatoid arthritis for up to 2 years. Based upon longer term
acceptability of the safety profile, the JADY study may be extended to allow
for continued baricitinib treatment for up to 5 years. Patients who completed
an originating study (Study JADA, JADZ, JADV, JADX, or JADW) may be eligible
for enrollment into Study JADY. Patients from future baricitinib RA studies
may also be enrolled into Study JADY. Planned enrollment will be approximately
2400 (if only the above mentioned studies are included) to 3000 patients (if
patients from future baricitinib studies are enrolled).
This study will consist of 3 parts: a screening period that will occur during
the last visit of the originating study; Part A: treatment period lasting up
to 2 years from enrollment into Study JADY; and Part B: posttreatment
follow-up period.
Patients will receive baricitinib 4 mg QD or baricitinib 2 mg QD.

Patients who have completed Study JADV, JADZ, JADX, or JADW will be assigned to
blinded baricitinib treatment (2 mg QD or 4 mg QD), and all patients who have
completed Study JADA will be assigned to receive open-label baricitinib 4 mg
QD. Patients with renal impairment at baseline of the originating study
(defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2) will
only be eligible for dosing with baricitinib 2 mg QD. Baricitinib tablets will
be administered orally.

Patients originating from Studies JADV, JADZ, JADX, or JADW and who were not
previously rescued will receive either a 4 mg or 2 mg matching placebo tablet
to maintain the blind of the step-down.

There may be risks or side effects either related to the drugs or the study
procedures.

As of 28 March 2012, 766 adults (188 healthy volunteers, 475 patients with
rheumatoid arthritis (RA), 67 subjects with
psoriasis (Ps), and 36 people with damaged kidneys) from 18 to 80 years of age,
plus 2 children with rare diseases,
have taken baricitinib.
Baricitinib is a molecule that blocks the effects of proteins in the body
called Janus kinases. Blocking these proteins
can affect the immune system. One effect may be a reduction in inflammatory and
autoimmune diseases such as
rheumatoid arthritis (RA), psoriasis (Ps), or diabetic nephropathy. Other drugs
that affect the immune system can
increase the risk of infection and cancer. Baricitinib may also increase these
risks.

A complete overview of the risks and discomforts related to the study drugs and
the study procedures can be found in
the patient information brochure.