A Multicenter, Open-Label Study of the Human Anti-TNF Monoclonal Antibody Adalimumab to Evaluate the Long Term Safety and Tolerability of Repeated Administration of Adalimumab in Subjects With Ulcerative Colitis

Ulcerative colitis is one of the two primary forms of idiopathic inflammatory
bowel disease. It is a chronic, relapsing inflammatory disease of the rectum
and/or large intestine characterized by inflammation and ulceration of the
mucosal and submucosal intestinal layers. The clinical course is marked by
exacerbation and remission. The incidence in Europe is estimated at 1.5 to 20.3
cases per 100,000 person-years. The aim of medical treatment in ulcerative
colitis is to induce and maintain remission.
Conventional pharmaceutical therapies do not completely abate the inflammatory
process and have significant side effects. Conventional therapies for the
induction of remission have included anti-inflammatory agents (5-ASA derivates
and corticosteroids) and the immunomodulatory agent cyclosporine. 5-ASA
derivates as well as immunomodulatory agents (azathiprine or 6-MP) have been
used for the maintenance of remission. Most recently, infliximab (a chimeric
monoclonal anti-TNF antibody) has demonstrated efficacy in subjects with
moderately to severely active ulcerative colitis and was approved in both
Europe and the US for the induction and maintenance of remission in subjects
with moderate to severe ulcerative colitis.

To evaluate the long term maintenance of response, safety and tolerability of
repeated
administration of adalimumab in subjects with Ulcerative Colitis who
participated in and successfully
completed Protocol M06-826 or Protocol M06-827.
The secondary objective is to assess pharmacokinetics (PK) of adalimumab
following subcutaneous adminstration.

The Day 1/Baseline visit for subjects entering M10-223 is Week 52 of studies
M06-826 or M06-827.
Subjects who enter this study from a blinded cohort will be assigned to
open-label adalimumab,
40 mg eow. Subjects who are inadequate responders (defined below) upon entering
the study who do
not show response during the study, or who showed a response and then have a
disease flare, may have
their adalimumab dose increased to 40 mg weekly, but no earlier than the Week
12 visit. If these
subjects continue to show inadequate response or continue to have a flare while
on 40 mg weekly
dosing, they may be discontinued from the study. Subjects who are clinical
responders or who are in
clinical remission and who subsequently experience a disease flare may have
their adalimumab dose
increased to every week dosing, but no earlier than the Week 12 visit. If these
subjects continue to have
a disease flare while on every week dosing, they may be discontinued from the
study.
Subjects who enter this study from an open-label cohort will continue their
previous dosing regimen of
every other week or weekly dosing. Subjects, entering the study who are
inadequate responders while
receiving 40 mg eow of adalimumab and who continue to show inadequate response,
may have their
dose frequency increased to 40 mg weekly at the Week 2 visit or thereafter.
Those subjects who
continue to be inadequate responders while receiving 40 mg weekly dosing may be
withdrawn from the
study.
Subjects entering the study on eow adalimumab dosing who are clinical
responders or who are in clinical
remission may have their adalimumab dose increased to every week dosing if they
subsequently
experience a disease flare (defined below). This dose increase may not occur
earlier than the Week 12
visit. If these subjects are still in disease flare while on every week dosing,
they may be discontinued
from the study. Subjects who enter the study on every week adalimumab dosing
and who subsequently
experience a disease flare may be withdrawn from the study.
Inadequate responder definition:
• Subjects with a Day 1/Baseline (M06-826 or M06-827 study) Partial Mayo Score
of 4-7 who
present with a score greater than or equal to their Baseline score on 2
consecutive visits at least
14 days apart
• Subjects with a Partial Mayo Score of 8 or 9 at Day 1/Baseline (M06-826 or
M06-827 study)
who present with a score of >= 7 on 2 consecutive visits at least 14 days apart
Disease Flare definition:
• Subject who present with a Partial Mayo Score difference of >= 3 compared to
the Day
1/Baseline (extension study) Partial Mayo Score on 2 consecutive visits at
least 14 days apart

The Day 1/Baseline visit for subjects entering M10-223 is Week 52 of studies
M06-826 or M06-827.

Subjects who enter this study from a blinded cohort will be assigned to
open-label adalimumab,
40 mg eow. Subjects who are inadequate responders (defined below) upon entering
the study who do
not show response during the study, or who showed a response and then have a
disease flare, may have
their adalimumab dose increased to 40 mg weekly, but no earlier than the Week
12 visit. If these
subjects continue to show inadequate response or continue to have a flare while
on 40 mg weekly
dosing, they may be discontinued from the study. Subjects who are clinical
responders or who are in
clinical remission and who subsequently experience a disease flare may have
their adalimumab dose
increased to every week dosing, but no earlier than the Week 12 visit. If these
subjects continue to have
a disease flare while on every week dosing, they may be discontinued from the
study.
Subjects who enter this study from an open-label cohort will continue their
previous dosing regimen of
every other week or weekly dosing. Subjects, entering the study who are
inadequate responders while
receiving 40 mg eow of adalimumab and who continue to show inadequate response,
may have their
dose frequency increased to 40 mg weekly at the Week 2 visit or thereafter.
Those subjects who
continue to be inadequate responders while receiving 40 mg weekly dosing may be
withdrawn from the
study.
Subjects entering the study on eow adalimumab dosing who are clinical
responders or who are in clinical
remission may have their adalimumab dose increased to every week dosing if they
subsequently
experience a disease flare (defined below). This dose increase may not occur
earlier than the Week 12
visit. If these subjects are still in disease flare while on every week dosing,
they may be discontinued
from the study. Subjects who enter the study on every week adalimumab dosing
and who subsequently
experience a disease flare may be withdrawn from the study.
Inadequate responder definition:
• Subjects with a Day 1/Baseline (M06-826 or M06-827 study) Partial Mayo Score
of 4-7 who
present with a score greater than or equal to their Baseline score on 2
consecutive visits at least
14 days apart
• Subjects with a Partial Mayo Score of 8 or 9 at Day 1/Baseline (M06-826 or
M06-827 study)
who present with a score of >= 7 on 2 consecutive visits at least 14 days apart
Disease Flare definition:
• Subject who present with a Partial Mayo Score difference of >= 3 compared to
the Day
1/Baseline (extension study) Partial Mayo Score on 2 consecutive visits at
least 14 days apart.

Beginning from week 96 in subjects who are in clinical response per Partial
Mayo Score compared to baseline for at least 2 consecutive visits at least 14
days apart the dose of adalimumab may be decreased to 40mg every other week,
at the discretion of the investigator using the IVR system.

Subjects who experience a disease flare or inadequate response may re-increase
their dose of adalimumab to 40 mg ew using the IVR system.

The subject may experience adverse events when the study drug is used. The most
common adverse events of Adalimumab injections were reactions at the injection
site. Subjects suffered from redness, itching, bruising, pain and/or swelling
of the injection site. Most injection site reactions were described as mild,
transient, and most of them disappeared without having to stop using the
medication. Other frequently reported site effects (rate of >=5%) of adalimumab
in subjects participating in the clinical studies in order of decreasing
frequency are: nasopharyngitis, upper respiratory infection, headache, nausea,
bronchitis, diarhea, cough, sinusitis, influenza, hypertension, urinary tract
infection, back pain, and rash.

Endoscopy risks
Preparation for the endoscopy may involve a limitation on the kinds of food you
may eat for 1-2 days prior to the test. Preparation for the endoscopy may also
involve the use of laxatives that may produce loose stools. Possible risks
during the endoscopy are getting a puncture (or hole) in the colon wall, which
may require surgery to correct, and bleeding that requires getting blood from
donors. The risk of the sedation medication, usually given during a
colonoscopy to help you relax, may cause allergic reactions such as nausea,
skin rash, dizziness with a drop in blood pressure, a slowing down of your
breathing.

Female must be either not of childbearing potential, defined as postmenopausal
for at least 1 year
prior to the previous study (M06-826 study or M06-827 study), or surgically
sterile (bilateral tubal
ligation, bilateral oophorectomy or hysterectomy), or is of childbearing
potential and practicing an
approved method of birth control throughout the study and for 150 days after
last dose of study drug.
Examples of approved methods of birth control include the following: Condoms,
sponge, foam, jellies, diaphragm or intrauterine device, oral, parenteral or
intravaginal contraceptives or a vasectomized partner.