A Phase 2b/3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Protocol to Evaluate the Efficacy and Safety of Guselkumab in Participants with Moderately to Severely Active Ulcerative Colitis (UC)

Guselkumab (CNTO 1959) is a fully human immunoglobulin G1 lambda monoclonal
antibody (mAb) that binds to human interleukin (IL)-23 with high affinity. The
binding of guselkumab to IL-23 blocks the binding of extracellular IL-23 to the
cell surface IL-23 receptor, inhibiting IL-23-specific intracellular signaling
and subsequent activation and cytokine production. In this manner, guselkumab
inhibits the biological activity of IL-23 in all in vitro assays examined.

The Phase 2b/3 clinical development program for guselkumab in ulcerative
colitis (UC) is designed to evaluate the safety and efficacy of guselkumab in
participants with moderately to severely active UC. Under this single protocol
(CNTO1959UCO3001), there are 3 separate studies:
* Induction Study 1 (Phase 2b Induction Dose-ranging Study)
* Induction Study 2 (Phase 3 Induction Study)
* Maintenance Study (Phase 3 Maintenance Study)
Participants who complete the Maintenance Study and who may benefit from
continued study intervention, in the opinion of the investigator, will have the
opportunity to participate in the long-term extension (LTE) of the Maintenance
Study and receive up to another 2 years of treatment.

Induction Study 1 (Phase 2b Induction Dose-ranging Study)
Objectives
Primary Objectives
The primary objectives of this study are, in participants with moderately to
severely active UC:
* To evaluate the efficacy of guselkumab as induction therapy.
* To evaluate the safety of guselkumab as induction therapy.
* To evaluate the dose-response of guselkumab to inform induction dose
selection for the Phase 3 induction study.
Secondary Objectives
The secondary objectives of this study are, in participants with moderately to
severely active UC:
* To evaluate the impact of guselkumab on health-related quality of life
(HRQoL) and health economics outcome measures.
* To evaluate the pharmacokinetics (PK), immunogenicity, and pharmacodynamics
(PD) of guselkumab therapy, including changes in C-reactive protein (CRP) and
fecal calprotectin.

Induction Study 2 (Phase 3 Induction Study)
Objectives
Primary Objectives
The primary objectives of this study are, in participants with moderately to
severely active UC:
* To evaluate the efficacy of guselkumab as induction therapy.
* To evaluate the safety of guselkumab as induction therapy.
Secondary Objectives
The secondary objectives of this study are, in participants with moderately to
severely active UC:
* To evaluate the impact of guselkumab on HRQoL and health economics outcome
measures.
* To evaluate the PK, immunogenicity, and PD of guselkumab therapy, including
changes in CRP and fecal calprotectin.

Maintenance Study (Phase 3 Maintenance Study)
Objectives
Primary Objectives
The primary objectives of this study are, in participants with moderately to
severely active UC who were induced into clinical response with guselkumab:
* To evaluate the efficacy of maintenance regimens of guselkumab.
* To evaluate the safety of maintenance regimens of guselkumab.
Secondary Objectives
The secondary objectives of this study are, in participants with moderately to
severely active UC who were induced into clinical response with guselkumab:
* To evaluate the impact of guselkumab on HRQoL and health economics outcome
measures.
* To evaluate the PK, immunogenicity, and PD of guselkumab therapy, including
changes in CRP and fecal calprotectin.

All 3 studies (Induction Study 1, Induction Study 2, Maintenance Study) under
this single protocol will be randomized, double-blind, placebo-controlled,
parallel-group, multicenter studies to evaluate the safety and efficacy of
guselkumab in participants with moderately to severely active UC. The induction
studies (Induction Study 1 and Induction Study 2) will target participants 18
years of age or older with moderately to severely active UC who have
demonstrated an inadequate response or failure to tolerate conventional (ie,
6-mercaptopurine [6-MP], azathioprine [AZA], or corticosteroids) or advanced
therapy (ADT; ie, tumor necrosis factor alpha [TNF*] antagonists, vedolizumab,
or tofacitinib). Participants who had an inadequate response or failure to
tolerate advanced therapy (ADT-Failure) will comprise a minimum of
approximately 40% and a maximum of approximately 50% of the population for the
following: 1) the first 200 participants randomized in Induction Study 1 for
the interim analysis and induction dose decision; and 2) the total population
of Induction Study 2. The Maintenance Study is a randomized withdrawal study
targeting participants with moderately to severely active UC who have
demonstrated a clinical response to guselkumab treatment in either Induction
Study 1 or Induction Study 2.
Overall, the program will evaluate guselkumab treatment through at least 64
weeks of induction and maintenance therapy. Participants who complete the
safety and efficacy evaluations at Week M-52 of the Maintenance Study and who
may benefit from continued study intervention, in the opinion of the
investigator, will have the opportunity to participate in the LTE of the
Maintenance Study for up to an additional 2 years of treatment (ie, Week M-52
to Week M 168) to evaluate the efficacy and safety of long-term maintenance
treatment.
All UC-specific medical therapies (ie, oral 5-aminosalicylic (5-ASA) compounds,
oral corticosteroids, 6 MP, AZA, or methotrexate [MTX]) must be maintained at a
stable dose through to the end of the induction studies and can only be
discontinued or reduced in dose if investigator judgment requires it because of
toxicity or medical necessity. The initiation or increase in dose of
UC-specific therapies (or any restricted/prohibited medication or therapy)
during Induction Study 1 or Induction Study 2 will prohibit a participant from
entering the Maintenance Study.
For participants who are receiving oral corticosteroids on entry in the
Maintenance Study, the investigator must begin tapering the daily dose of
corticosteroids at Week M-0. Other UC-specific medical therapies (ie, oral
5-ASA compounds, 6-MP, AZA, or MTX) must be maintained at stable doses through
Week M 52 unless investigator judgment requires that the therapy be
discontinued, or the dose reduced because of toxicity or medical necessity.
Tapering of the daily dose of corticosteroids may be paused for participants
meeting clinical flare criteria. Participants meeting criteria for loss of
clinical response during the Maintenance Study will be eligible for a single
blinded dose adjustment as described in the protocol.
During Induction Study 1, an interim analysis of the first 200 randomized
participants who have completed the Week I-12 visit or have terminated study
participation prior to Week I-12 will be performed. The purpose of this interim
analysis is to select a single induction dose for confirmatory evaluation in
the Phase 3 induction study (Induction Study 2). A Dose Selection Committee,
composed of sponsor management representatives from Clinical, Safety,
Biostatistics, and Clinical Pharmacology, who are not associated with study
conduct, will be responsible for selecting the induction dose of guselkumab to
be evaluated in Induction Study 2. While the data from the first 200 randomized
participants is being evaluated, participants will continue to be enrolled in
Induction Study 1, up to a maximum of 440 participants. Once the induction dose
selection has occurred, participants will begin randomization into Induction
Study 2.
Efficacy, safety, PK, immunogenicity, and biomarkers will be assessed at time
points indicated in the appropriate Schedule of Activities (SoA).
An external, independent Data Monitoring Committee (DMC), with defined roles
and responsibilities as governed by a DMC charter, will assess the safety of
participants across the 3 studies.

At Weeks I-12 and/or I-24 of Induction Study 1 and Induction Study 2,
participants will be evaluated for clinical response. Eligibility for the
Maintenance Study will be determined by the participant's clinical response
status.
*
Induction Study 1 (Phase 2b Induction Dose-ranging Study)
From Week I-0 Through Week I-12
In Induction Study 1, participants will be randomized to 1 of 4 study
intervention groups as described below. Participants will remain on their
assigned study intervention through Week I 12..
* Guselkumab 400 mg IV: Participants will receive guselkumab 400 mg IV at Weeks
I-0, I-4, and I-8 (ie, 3 IV doses).
* Guselkumab 200 mg IV: Participants will receive guselkumab 200 mg IV at Weeks
I-0, I-4, and I-8 (ie, 3 IV doses).
* Placebo: Participants will receive placebo IV at Weeks I-0, I-4, and I-8 (ie,
3 IV doses).
From Week I-12 Through Week I-24
Guselkumab
For participants who received 3 IV guselkumab doses (400 mg or 200 mg),
subsequent study intervention will be based on clinical response status at Week
I-12 as follows:
* Guselkumab clinical responders at Week I-12: Participants will enter the
Maintenance Study and will be re-randomized to either receive guselkumab 200 mg
subcutaneously (SC) every 4 weeks (q4w), guselkumab 100 mg SC every 8 weeks
(q8w), or placebo.
* Guselkumab clinical nonresponders at Week I-12: Participants will receive
guselkumab 200 mg SC at Weeks I-12, I-16, and I-20. Placebo IV will also be
administered at Weeks I 12, I 16, and I-20 to maintain the blind.
At Week I-24, subsequent study intervention will be based on clinical response
status as follows:
* Guselkumab clinical responders at Week I-24 (ie, delayed responders to
guselkumab): Participants will enter the Maintenance Study and will receive
guselkumab 200 mg SC q4w.
* Guselkumab clinical nonresponders at Week I-24: Participants will discontinue
study intervention.
Placebo
For participants who received 3 IV placebo doses, subsequent study intervention
will be based on clinical response status at Week I-12 as follows:
* Placebo clinical responders at Week I-12: Participants will enter the
Maintenance Study and receive placebo SC q4w.
* Placebo clinical nonresponders at Week I-12: Participants will receive
guselkumab 200 mg IV at Weeks I-12, I-16, and I-20. Placebo SC will also be
administered at Weeks I-12, I-16, and I-20 to maintain the blind.
At Week I-24, subsequent study intervention will be based on clinical response
status as follows:
* Guselkumab clinical responders at Week I-24 (ie, placebo crossover
responders): Participants will enter the Maintenance Study and will be
rerandomized to either receive guselkumab 200 mg SC q4w, guselkumab 100 mg q8w,
or placebo.
* Guselkumab clinical nonresponders at Week I-24: Participants will discontinue
study intervention.

Induction Study 2 (Phase 3 Induction Study)
In Induction Study 2, participants will be randomized to 1 of 2 study
intervention groups as described below. Participants will remain on their
assigned study intervention through Week I 12.
Guselkumab Induction Dose Regimen
Selection of the Phase 3 guselkumab induction dose for Induction Study 2 will
be based on an interim analysis of Induction Study 1. The participants will
receive study intervention at Weeks I-0, I-4, and I-8 (ie, 3 IV doses).
At Week I-12, subsequent study intervention will be based on clinical response
status as follows:
* Guselkumab clinical responders at Week I-12: Participants will enter the
Maintenance Study and will be rerandomized to either receive guselkumab 200 mg
SC q4w, guselkumab 100 mg q8w, or placebo.
* Guselkumab clinical nonresponders at Week I-12: Participants will receive
guselkumab 200 mg SC at Weeks I-12, I-16, and I-20. Placebo IV will also be
administered at Weeks I 12, I 16, and I-20 to maintain the blind.
At Week I-24, subsequent study intervention will be based on clinical response
status as follows:
* Guselkumab clinical responders at Week I-24 (ie, guselkumab 24 week
respônders): Participants will enter the Maintenance Study and will receive
guselkumab 200 mg SC q4w.
* Guselkumab clinical nonresponders at Week I-24: Participants will discontinue
study intervention.
Placebo
Participants will receive placebo IV at Weeks I-0, I-4, and I-8 (ie, 3 IV
doses).
At Week I-12, subsequent study intervention will be based on clinical response
status as follows:
* Placebo clinical responders at Week I-12: Participants will enter the
Maintenance Study and receive placebo SC q4w.
* Placebo clinical nonresponders at Week I-12: Participants will receive the
Phase 3 guselkumab induction IV dose at Weeks I-12, I-16, and I-20. Placebo SC
will also be administered at Weeks I-12, I-16, and I-20 to maintain the blind.
At Week I-24, subsequent study intervention will be based on clinical response
status as follows:
* Guselkumab clinical responders at Week I-24 (ie, placebo crossover
responders): Participants will enter the Maintenance Study and will be
rerandomized to either receive guselkumab 200 mg SC q4w, guselkumab 100 mg q8w,
or placebo.
* Guselkumab clinical nonresponders at Week I-24: Participants will discontinue
study intervention.

Maintenance Study (Phase 3 Maintenance Study)
In the Maintenance Study, the randomized population (ie, the primary analysis
population) will include guselkumab clinical responders at Week I-12 and
placebo crossover responders at Week I-24 from Induction Study 1 or Induction
Study 2. These participants will be rerandomized to 1 of 3 study intervention
groups as described below.
* Guselkumab 200 mg SC q4w: Participants will receive guselkumab 200 mg SC q4w
starting at Week M-0 through Week M-44.
* Guselkumab 100 mg SC q8w: Participants will receive guselkumab 100 mg SC q8w
starting at Week M-4 through Week M-44. Placebo SC will also be administered at
alternate visits to maintain the blind.
* Placebo: Participants will receive placebo SC q4w starting at Week M-0
through Week M 44.
Participants will remain on their assigned study intervention through Week
M-44. Participants who subsequently meet criteria for loss of clinical response
will be eligible for a single blinded dose adjustment as described in the
protocol.
In the Maintenance Study, the nonrandomized population will consist of delayed
responders to guselkumab at Week I-24 and placebo responders at Week I-12.
Delayed responders to guselkumab at Week I-24 will receive guselkumab 200 mg SC
q4w starting at Week M-0 through Week M-44. Placebo responders at Week I-12
will receive placebo SC q4w starting at Week M-0 through Week M-44. These
populations are not eligible for dose adjustment.

Side effects (application) study medication, possible side effects/discomforts
of the evaluations in the study, unknown risks.


Potential risks of guselkumab, including those of serious infection and
malignancy, are being
addressed via judicious inclusion/exclusion criteria, frequent study visits to
allow for close
monitoring of patient safety, guidelines for participant management (including
monitoring of
clinical laboratory tests and treatment discontinuation criteria), detailed
description of allowed
and prohibited concomitant medications, and comprehensive medical monitoring of
data by the
sponsor during the conduct of the studies. In addition, a comprehensive safety
monitoring plan
with oversight from an external, independent Data Monitoring Committee (DMC)
will be
implemented to ensure the safety of guselkumab in participants with moderately
to severely
active UC.