A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Protocol to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Subjects with Moderately to Severely Active Ulcerative Colitis

Ustekinumab (STELARA®) is a fully human immunoglobulin G1 kappa (IgG1k)
monoclonal antibody to human interleukin (IL)-12/23p40 that binds with high
affinity to human IL-12 and IL-23. Ustekinumab prevents IL-12 and IL-23
bioactivity by preventing their interaction with their cell surface IL-12R*1
receptor protein. Through this mechanism of action, ustekinumab effectively
neutralizes IL-12 (Th1)- and IL-23 (Th17)-mediated cellular responses. Abnormal
regulation of IL-12 and IL-23 has been associated with multiple immune-mediated
diseases, including inflammatory bowel disease (IBD). Therefore, binding and
inhibiting the IL-12/23p40 subunit may provide effective therapy in IBD,
including Crohn's disease and ulcerative colitis (UC).
Ustekinumab has received marketing approval globally, including countries in
North America, Europe, South America, and the Asia-Pacific region, for the
treatment of adult patients with chronic moderate to severe plaque psoriasis or
active psoriatic arthritis. Ustekinumab is currently being evaluated in a Phase
3 development program for Crohn*s disease.
Data from completed Phase 2 studies of ustekinumab in Crohn*s disease, along
with the shared biology and the similar response to current treatments between
Crohn*s disease and UC, provide a substantial scientific and clinical rationale
to justify a direct-to-Phase-3 approach to the study of ustekinumab in UC.
Relative to approved therapies for UC (ie, tumor necrosis factor antagonists
and the anti-*4*7 integrin antagonist, vedolizumab), ustekinumab offers the
potential for a more convenient treatment regimen, with subcutaneous (SC)
administration every 8 to 12 weeks during maintenance, as well as a novel
mechanism of action in the treatment of UC, and a documented long-term safety
profile.
The Phase 3 development program for ustekinumab in the treatment of UC will be
conducted under a single protocol but will be designed and analyzed as 2
separate studies, an induction study and a maintenance study.

INDUCTION STUDY
Primary Objectives:
* To evaluate the efficacy of intravenous (IV) ustekinumab in inducing clinical
remission in subjects with moderately to severely active UC.
* To evaluate the safety of IV ustekinumab in subjects with moderately to
severely active UC.

MAINTENANCE STUDY
Primary Objectives:
* To evaluate clinical remission for SC maintenance regimens of ustekinumab in
subjects with moderately to severely active UC induced into clinical response
with ustekinumab.
* To evaluate the safety of SC maintenance regimens of ustekinumab in subjects
with moderately to severely active UC induced into clinical response with
ustekinumab.

Exploratory Objective in Induction and Maintenance:
* To evaluate response using the Mayo score without the physician's global
assessment (PGA) subscore.

The Phase 3 development program for ustekinumab in the treatment of UC will be
conducted under a single protocol but will be designed and analyzed as 2
separate studies, an induction study and a maintenance study. Both will be
Phase 3, randomized, double-blind, placebo-controlled, parallel-group,
multicenter studies of ustekinumab in subjects with moderately to severely
active UC. The induction study will target subjects with moderately to severely
active UC who demonstrate an inadequate response or failure to tolerate
conventional or biologic therapy. The maintenance study will be a randomized
withdrawal study targeting subjects with moderately to severely active UC who
demonstrate a clinical response to induction treatment with IV ustekinumab.
Overall, the program will evaluate ustekinumab treatment in subjects with
moderately to severely active UC through at least 1 year of induction and
maintenance therapy. After completion of the maintenance study through Week 44,
a long-term extension (LTE) will follow eligible subjects for an additional 3
years.
Throughout the induction and maintenance studies, efficacy, PK, biomarkers, and
safety will be assessed at timepoints indicated in the appropriate Time and
Events Schedules.
Blood samples for pharmacogenomic analyses will be collected from subjects who
consent separately to this component of the study (where local regulations
permit). Subject participation in pharmacogenomic research is optional.
An interim analysis to assess for futility is planned when the first 30% of
subjects randomized in the induction study either complete the induction Week 8
visit or terminate study participation before Week 8.
An independent Data Monitoring Committee will be commissioned for this study.
The end of the CNTO1275UCO3001 study is defined as the date on which the last
subject completes the last visit in the LTE.

Induction: A target of 951 subjects will be randomized in a 1:1:1 ratio to 1 of
3 treatment groups and will receive their assigned IV dose of study agent at
Week 0:
* Placebo IV
* Ustekinumab 130 mg IV
* Weight-range-based ustekinumab doses approximating ustekinumab 6 mg/kg IV
(ie, ustekinumab ~6 mg/kg IV):
*Ustekinumab 260 mg (weight *55 kg)
*Ustekinumab 390 mg (weight >55 kg but *85 kg)
*Ustekinumab 520 mg (weight >85 kg)
At Week 8, all subjects will be evaluated for the primary endpoint of clinical
remission, and for clinical response. Further study agent administration will
be determined by clinical response status (using the Mayo endoscopy subscore
assigned by the local endoscopist) at Week 8, as follows:
* Subjects who are in clinical response at Week 8 are eligible to enter the
maintenance study.
* Subjects who are not in clinical response at Week 8 will receive ustekinumab
as follows:
*Subjects who were randomized to placebo at Week 0 will receive 1 dose of
ustekinumab ~6 mg/kg IV plus placebo SC (to maintain the blind) at Week 8.
*Subjects who were randomized to ustekinumab at Week 0 will receive 1 dose of
ustekinumab 90 mg SC plus placebo IV (to maintain the blind) at Week 8.
At Week 16, the subjects who were not in clinical response at Week 8 will be
re-evaluated for clinical response (clinical response status will be based on
the Mayo endoscopy subscore assigned by the local endoscopist):
*Subjects who achieve clinical response at Week 16 are eligible to enter the
maintenance study.
*Subjects who do not achieve clinical response at Week 16 will not enter the
maintenance study and will have a safety follow-up visit approximately 20 weeks
after their last (ie, Week 8) administration of study agent.
Maintenance: A target of 327 subjects who are in clinical response to IV
ustekinumab induction will be randomized in a 1:1:1 ratio to 1 of 3 treatment
groups and will receive their assigned SC dose of study agent at maintenance
Week 0:
* Placebo SC
* Ustekinumab 90 mg SC every 12 weeks (q12w)
* Ustekinumab 90 mg SC every 8 weeks (q8w)
Subjects who were in clinical response to IV ustekinumab during induction will
comprise the primary population in the maintenance study:
* Subjects who were randomized to receive ustekinumab at Week 0 of the
induction study and were in clinical response at induction Week 8.
* Subjects who were randomized to receive placebo at Week 0 of the induction
study and were not in clinical response at induction Week 8, but were in
clinical response at induction Week 16 after receiving a dose of IV ustekinumab
at induction Week 8.
Additional subjects entering the maintenance study will include the following;
these subjects will not be part of the primary population:
* Subjects who are in clinical response to placebo IV induction will receive
placebo SC.
* Subjects who were delayed responders to ustekinumab induction (ie, were not
in clinical response at induction Week 8 but were in clinical response at
induction Week 16) will receive ustekinumab 90 mg SC q8w.

All subjects will receive their assigned dose of SC study agent at maintenance
Week 0. Thereafter, to maintain the blind, all subjects will receive study
agent at all scheduled study agent administration visits specified in the Time
and Events Schedule for maintenance. Subjects will be assessed for clinical
flare at every visit.

Number of blood draws: 58 x 7,07 ml per visit = 410 ml in total. Patient might
experience discomfort from needle during blood draw.
Number of visits to the study doctor/hospital: 58 visits.
Intravenous injections: 2 x 250 ml. Patient might experience local discomfort
from needle during IV injection.
Subcutaneous injections: 50 x 1 ml. Patient might experience local discomfort
from needle during SC injection.
Physical examination: 6 times throughout the study. Patient might not
experience any burden or risk from phys. examination.
Questionnaires: will be given to patient to fill out, in total 8 times during
the study.
Mayo diary: will be given to patient to maintain throughout the study; patient
to return diary to study doctor 21 times during study.
Bristol Stool Form diary: will be given to patient during the induction part of
the study to maintain throughout the study; patient to return diary to study
doctor 5 times during study.
Physical discomfort of ECG: patient might experience local discomfort from the
sticky padges (1 time during the study).
Physical discomfort of Chest X-ray: patient might not experience any discomfort
from chest x-ray (1 time during the study).
Physical discomfort of endoscopy with biopsy: patient might experience
discomfort from the tube when this is inserted in the rectum into the colon (5
times during the study).
Potential adverse effects of treatment: reported side effects of study
medication.
Potential effect of use of placebo: possibly patient might not have a clinical
benefit when receiving placebo.
Stool sample collection: 13 times throughout the study. Patient might
experience this as a burden to collect his/her stool sample.