Ulcerative Colitis

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: x To evaluate the efficacy of guselkumab as induction therapy. x To evaluate the safety of guselkumab as induction therapy. x To evaluate the dose-response of guselkumab to inform induction dose selection for the Phase 3 induction study. 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: x To evaluate the efficacy of guselkumab as induction therapy. x To evaluate the safety of guselkumab as induction therapy. 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: x To evaluate the efficacy of maintenance regimens of guselkumab. x To evaluate the safety of maintenance regimens of guselkumab.

Guselkumab/placebo

Guselkumab

Pre-filled syringes

100 mg/ml

Induction Study 1 (Phase 2b Induction Dose-ranging Study)
Primary Endpoint
The primary endpoint in this study is clinical response at Induction Week 12 (Week I-12).

Induction Study 2 (Phase 3 Induction Study)
Endpoints
All endpoints will evaluate the efficacy of guselkumab versus placebo, in participants with moderately to
severely active UC.

Maintenance Study (Phase 3 Maintenance Study)
Primary Endpoint
The primary endpoint in this study is clinical remission at Maintenance Week 44 (Week M-44).

Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in Induction Study
1 or Induction Study 2:
1. Male or female, 18 years of age or older.
2. Documented diagnosis (histological and either endoscopic or radiographic) of UC at least
3 months prior to screening. A biopsy report supporting the diagnosis must be available
in the source documents.
3. Moderately to severely active UC, defined as a baseline (Week I-0) modified Mayo score
of 4 to 9, inclusive, using the Mayo endoscopy subscore obtained during the central
review of the video endoscopy.
4. Mayo rectal bleeding subscore ≥1 at baseline.
5. Screening endoscopy with ≥2 on the endoscopy subscore of the Mayo score as obtained
during the central review of the video endoscopy.
6. A participant who had extensive colitis for ≥8 years, or disease limited to the left side of
the colon for ≥10 years, must either have had a full colonoscopy to assess for the presence
of dysplasia within 1 year before the first dose of study intervention or a full colonoscopy
to assess for the presence of malignancy at the screening visit.
7. A participant ≥45 years of age must either have had a full colonoscopy to assess for the
presence of adenomatous polyps within 5 years before the first dose of study intervention
or a full colonoscopy to assess for the presence of adenomatous polyps at the screening
visit. The adenomatous polyps must be removed before the first dose of study
intervention.
Concomitant or previous medical therapies received
8. A participant must:
a. Have failed an advanced therapy, ie, have received treatment with 1 or more TNFα
antagonists, vedolizumab, or tofacitinib at a dose approved for the treatment of
UC, and have a documented history of failure to respond to or tolerate such
treatment as defined in Appendix 2 (Section 10.2) and Appendix 3 (Section 10.3);
OR
b. Be naïve to advanced therapy (ie, TNFα antagonists, vedolizumab, and tofacitinib)
or not have demonstrated a history of failure to respond to, or tolerate, advanced
therapy and have a prior or current UC medication history that includes at least 1
of the following:
1) Inadequate response to or failure to tolerate current treatment with oral
corticosteroids or immunomodulators (6-MP or AZA) as defined in Appendix
4 (Section 10.4).
OR
2) History of failure to respond to, or tolerate, at least 1 of the following
therapies: oral or IV corticosteroids or immunomodulators (6-MP or AZA) as
defined in Appendix 4 (Section 10.4).
OR
3) History of corticosteroid dependence (ie, an inability to successfully taper
corticosteroids without a return of the symptoms of UC) as defined in
Appendix 4 (Section 10.4).
9. Before the first dose of study intervention, the following conditions must be met:
a. If receiving conventional immunomodulators (ie, AZA, 6-MP, or MTX), must
have been taking them for ≥12 weeks, and on a stable dose for at least 4 weeks.
b. If AZA, 6-MP, or MTX has been recently discontinued, it must have been
stopped for at least 4 weeks.
c. If receiving oral 5-ASA compounds, the dose must have been stable for at least
2 weeks.
d. If receiving oral corticosteroids other than budesonide or beclomethasone
dipropionate, the dose must be ≤20 mg/day prednisone or its equivalent and must
have been stable for at least 2 weeks.
e. If receiving oral budesonide or beclomethasone dipropionate, the dose must have
been stable for at least 2 weeks.
f. If oral 5-ASA compounds or oral corticosteroids have been recently
discontinued, they must have been stopped for at least 2 weeks.
10. The following medications/therapies must have been discontinued before the first dose of
study intervention:
a. Vedolizumab for at least 12 weeks.
b. Tofacitinib and other inhibitors of JAK for at least 2 weeks or 5 half-lives,
whichever is longer.
c. TNFα-antagonist therapy (eg, infliximab, adalimumab, or golimumab [or
approved biosimilars for these therapies]) for at least 8 weeks.
d. Cyclosporine, mycophenolate mofetil, tacrolimus, or sirolimus for at least
4 weeks.
e. 6-thioguanine must have been discontinued for at least 4 weeks.
f. Rectal corticosteroids (ie, corticosteroids administered to the rectum or sigmoid
colon via foam or enema or suppository) for at least 2 weeks.
g. Rectal 5-ASA compounds (ie, 5-ASAs administered to the rectum or sigmoid
colon via foam or enema or suppository) for at least 2 weeks.
h. Parenteral corticosteroids for at least 2 weeks.
i. Total parenteral nutrition or enteral nutrition for at least 2 weeks.
j. Antibiotics for the primary treatment of UC (eg, ciprofloxacin, metronidazole,
or rifaximin) for at least 2 weeks.
Screening laboratory tests
11. Screening laboratory test results within the following parameters, and if 1 or more of the
laboratory parameters is out of range, a single retest of laboratory values is permitted
during the approximately 8-week screening period:
a. Hemoglobin ≥8.0 g/dL (International System of Units [SI]: ≥80.0 g/L)
b. White blood cell count (WBC) ≥3 × 103 cells/µL (SI: ≥3.0 × 109 cells/L)
c. Neutrophils ≥1.5 × 103 cells/µL (SI: ≥1.5 × 109 cells/L)
d. Platelets ≥100 × 103 cells/µL (SI: ≥100 × 109 cells/L)
e. Serum creatinine ≤1.5 mg/dL (SI: ≤133 µmol/L)
f. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
concentrations must be ≤2 times the upper limit of the normal range for the
laboratory conducting the test.
g. Direct (conjugated) bilirubin <1.0 mg/dL.
Tuberculosis
12. Is considered eligible according to the following TB screening criteria:
a. Has no history of latent or active TB before screening. An exception is made for
participants who have a history of latent TB AND satisfy one of the following
criteria:
1) are currently receiving treatment for latent TB
OR
2) will initiate treatment for latent TB before the first dose of study intervention
OR
3) have documentation of having completed appropriate treatment for latent TB
within 5 years before the first dose of study intervention. It is the responsibility
of the investigator to verify the adequacy of previous anti-tuberculous
treatment and provide appropriate documentation. Patients with a history and
documentation of having completed appropriate treatment for latent TB more
than 5 years before the first dose of study intervention are not eligible.
b. Has no signs or symptoms suggestive of active TB based on medical history
and/or physical examination.
c. Has had no recent close contact with a person with active TB or, if there has
been such contact, will be referred to a physician specializing in TB to undergo
additional evaluation and, if warranted, receive appropriate treatment for latent
TB before the first dose of study intervention.
d. Within 8 weeks prior to the first dose of study intervention, have a negative
QuantiFERON-TB® (or T-SPOT® for sites in Japan) test result, or have a newly
identified positive QuantiFERON-TB® test (or T-SPOT® for sites in Japan) in
which active TB has been ruled out and for which appropriate treatment for latent
TB has been initiated prior to the first dose of study intervention (see
Section 8.2.11). Indeterminate or borderline results should have the test repeated
as described in Section 8.2.11.
Note: A negative tuberculin skin test result (see Appendix 5 [Section 10.5]) is
additionally required if the QuantiFERON-TB® test is not approved/registered in the
country in which this protocol is being conducted. In Ukraine, while the
QuantiFERON-TB® test is not approved/registered, it is acceptable, and an additional
tuberculin skin test is not required. The QuantiFERON-TB® (or T-SPOT® for sites
in Japan) test and the tuberculin skin test are not required at screening for participants
with a history of latent TB, if active TB has been ruled out, and if appropriate
treatment has been initiated/completed as described above in Inclusion Criterion
#12a.
e. Criterion modified per Amendment 1.
e.1. Has a chest radiograph (both posterior-anterior and lateral views, or per
country regulations where applicable), taken within 12 weeks before the first
dose of study intervention and read by a qualified radiologist or qualified
pulmonologist according to local clinical practice, with no evidence of current,
active TB or old, inactive TB. A chest CT scan is also acceptable if obtained
instead of a chest radiograph outside of the protocol.
Contraception
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should
be consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
13. A woman of childbearing potential must have a negative urine pregnancy test at screening
and at Week 0.
14. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for 12 weeks after the last dose of study intervention.
15. Before randomization, a woman must be (as defined in Appendix 6 [Section 10.6],
Contraceptive and Barrier Guidance and Collection of Pregnancy Information):
a. Not of childbearing potential
OR
b. Of childbearing potential and:
o If heterosexually active, practicing a highly effective method of
contraception (failure rate of <1% per year when used consistently and
correctly) and agrees to remain on a highly effective method while receiving
study intervention and until 12 weeks after last dose (ie, the end of relevant
systemic exposure). Examples of highly effective methods of contraception
are located in Appendix 6 (Section 10.6), Contraceptive and Barrier
Guidance and Collection of Pregnancy Information; however, the method
selected must meet local/regional regulations/guidelines for highly effective
contraception.
Note: If a participant’s childbearing potential changes after start of the study (eg, a
premenarchal woman experiences menarche) or the risk of pregnancy changes (eg, a
woman who is not heterosexually active becomes active), a woman must begin using a
highly effective method of contraception, as described above.
16. A man who is sexually active with a woman of childbearing potential and who has not
had a vasectomy must agree to use a barrier method of birth control, eg, either condom
with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
17. A male participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum of 12 weeks after receiving the last dose of study
intervention.
General
18. Must sign an ICF indicating that he or she understands the purpose of, and procedures
required for, the study and is willing to participate in the study. In regions where the legal
age of consent is older than 18 years, informed consent must be obtained from and signed
by both the participant and his or her legally acceptable representative.
19. Must sign a separate ICF if he or she agrees to provide optional DNA samples for research
where local regulations permit. In regions where the legal age of consent is older than 18
years, informed consent must be obtained from and signed by both the participant and his
or her legally acceptable representative. Refusal to give consent for the optional DNA
samples does not exclude a participant from participation in the study.
20. Must be willing and able to adhere to all specified requirements, including but not limited
to completion of the required assessments, adherence to the visit schedule, and
compliance with the lifestyle restrictions as specified in this protocol.

Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in Induction Study 1 or Induction Study 2:
1. Severe extensive colitis as evidenced by:
a. Current hospitalization for the treatment of UC.
OR
b. Investigator judgment that the participant is likely to require a colectomy within
12 weeks of baseline.
OR
c. Symptom complex at screening or baseline visits that includes at least 4 of the
following:
1) Diarrhea with ≥6 bowel movements/day with macroscopic blood in stool
2) Focal severe or rebound abdominal tenderness
3) Persistent fever (temperature ≥38°C)
4) Tachycardia (>100 beats/minute)
5) Anemia (hemoglobin <8.5 g/dL)
2. UC limited to the rectum only or to <20 cm of the colon.
3. Presence of a stoma.
4. Presence or history of a fistula.
5. Require, or required within the 2 months before screening, surgery for active
gastrointestinal bleeding, peritonitis, intestinal obstruction, or intra-abdominal or
pancreatic abscess requiring surgical drainage, or other conditions possibly
confounding the evaluation of benefit from study intervention treatment.
6. Presence of symptomatic colonic or small bowel obstruction, confirmed by objective
radiographic or endoscopic evidence of a stricture with resulting obstruction (dilation
of the colon or small bowel proximal to the stricture on barium radiograph or an inability
to traverse the stricture at endoscopy).
7. History of extensive colonic resection (eg, less than 30 cm of colon remaining) that
would prevent adequate evaluation of the effect of study intervention on clinical disease
activity.
8. History of colonic mucosal dysplasia. Participants will not be excluded from the study
because of a pathology finding of “indefinite for dysplasia with reactive atypia.”
9. Presence on screening endoscopy of adenomatous colonic polyps, if not removed before
study entry, or history of adenomatous colonic polyps that were not removed.
10. Diagnosis of indeterminate colitis, microscopic colitis, ischemic colitis, or Crohn’s
disease or clinical findings suggestive of Crohn’s disease.
11. Criterion modified per Amendment 1.
11.1 Stool culture or other examination positive for an enteric pathogen, including
Clostridium difficile toxin, within 4 months before the first dose of study intervention,
unless a repeat examination is negative and there are no signs of ongoing infection with
that pathogen. Note: If time allows, treatment and repeat testing can occur in the current
screening period.
Concomitant or previous medical therapies received
12. Has received the following prescribed medications or therapies:
a. A biologic therapy targeted at IL-12 and/or IL-23 (eg, ustekinumab,
briakinumab, guselkumab, mirikizumab, tildrakizumab, brazikumab, or
risankizumab).
b. Natalizumab within 12 months of the first dose of study intervention.
c. Agents that deplete B or T cells (eg, rituximab, alemtuzumab) within
12 months of the first dose of study intervention or continue to manifest
depletion of B or T cells more than 12 months after completion of therapy with
lymphocyte-depleting agents.
d. Any investigational drug/therapy within 4 weeks before the first dose of study
intervention or within 5 half-lives of the investigational agent, whichever is
longer.
e. Apheresis (eg, Adacolumn or Cellsorba apheresis) within 2 weeks before the
first dose of study intervention.
f. Fecal microbiota transplantation within 12 weeks before the first dose of study
intervention.
Infections or predisposition to infections
13. History of latent or active granulomatous infection, including histoplasmosis or
coccidioidomycosis, before screening. Refer to Inclusion Criterion #12 for information
regarding eligibility with a history of latent TB.
14. History of, or ongoing, chronic or recurrent infectious disease, including but not limited
to, recurrent sinopulmonary infections, bronchiectasis, recurrent renal/urinary tract
infection (eg, recurrent pyelonephritis, recurrent cystitis), an open, draining, or infected
skin wound, or an ulcer.
15. Chest radiograph within 12 weeks before the first dose of study intervention that shows
an abnormality suggestive of a malignancy or current active infection, including TB.
16. History of being human immunodeficiency virus (HIV) antibody-positive, or tests
positive for HIV at screening.
17. Is seropositive for antibodies to hepatitis C virus (HCV), unless they satisfy 1 of the
following conditions:
a. Has a history of successful treatment, defined as being negative for HCV RNA
at least 24 weeks after completing antiviral treatment, and has a negative HCV
RNA test result at screening,
OR
b. While seropositive, has a negative HCV RNA test result at least 24 weeks prior
to screening and a negative HCV RNA test at the screening.
18. Tests positive for hepatitis B virus (HBV) infection, see (Appendix 7 [Section 10.7]).
Note: For participants who are not eligible for this study due to HIV, HCV, and HBV
test results, consultation with a physician with expertise in the treatment of those
infections is recommended.
19. Bacille Calmette-guérin (BCG) vaccination within 12 months or any other live bacterial
or live viral vaccination within 12 weeks of baseline.
20. Has or has had a nontuberculous mycobacterial infection or clinically significant
opportunistic infection (eg, cytomegalovirus colitis, pneumocystosis, invasive
aspergillosis).
21. Has had a clinically significant infection (eg, hepatitis, sepsis, pneumonia,
pyelonephritis), has been hospitalized for an infection, or has been treated with
parenteral antibiotics for an infection within 2 months before the first dose of study
intervention. Treated and resolved infections not considered clinically significant at the
discretion of the investigator need not be exclusionary (eg, acute upper respiratory tract
infection, uncomplicated urinary tract infection).
22. Evidence of a herpes zoster infection within 8 weeks of baseline.
Malignancy or increased potential for malignancy
23. Currently has a malignancy or has a history of malignancy within 5 years before
screening (with the exception of a nonmelanoma skin cancer that has been adequately
treated with no evidence of recurrence for at least 3 months [defined as a minimum of
12 weeks] before the first dose of study intervention or cervical carcinoma in situ that
has been treated with no evidence of recurrence for at least 3 months before the first
dose of study intervention).
24. History of lymphoproliferative disease, including lymphoma; a history of monoclonal
gammopathy of undetermined significance; or signs and symptoms suggestive of
possible lymphoproliferative disease, such as lymphadenopathy or splenomegaly.
Coexisting medical conditions or past medical history
25. History of severe, progressive, or uncontrolled renal, genitourinary, hepatic,
hematologic, endocrine, cardiac, vascular, pulmonary, rheumatologic, neurologic,
psychiatric, or metabolic disturbances, or signs and symptoms thereof.
26. Transplanted organ (with the exception of a corneal transplant performed >12 weeks
before screening).
27. Poor tolerability of venipuncture or lacks adequate venous access for required blood
sample collections during the study period.
28. History of drug or alcohol abuse according to the Diagnostic and Statistical Manual of
Mental Disorders, 5th edition (DSM-V), within 1 year before screening.
29. Unstable suicidal ideation or suicidal behavior in the last 6 months that may be defined
as a Columbia-Suicide Severity Rating Scale (C-SSRS) rating at screening of: Suicidal
Ideation with Intention to Act (“Ideation level 4”), Suicidal Ideation with Specific Plan
and Intent (“Ideation level 5”), or suicidal behavior (actual suicide attempt, interrupted
suicide attempt, aborted suicide attempt, or preparatory behaviors for making a suicide
attempt), and is considered to be at risk by the investigator based on an evaluation by a
mental health professional. In addition, participants with C-SSRS ratings of Wish to be
Dead (“Ideation level 1”), Non-Specific Active Suicidal Thoughts (“Ideation level 2”),
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act (“Ideation
level 3”), or non-suicidal self-injurious behavior who are determined to be at risk by the
investigator may not be randomized.
30. Known allergy, hypersensitivity, or intolerance to guselkumab or its excipients (refer to
the guselkumab IB).
31. Is a woman who is pregnant, or breastfeeding, or planning to become pregnant while
enrolled in this study or within 12 weeks after the last dose of study intervention.
32. Is a man who plans to father a child while enrolled in this study or within 12 weeks after
the last dose of study intervention.
General
33. Currently participating or intends to participate in any other study using an
investigational agent or procedure during the conduct of this study.
34. Has any condition for which, in the opinion of the investigator, participation would not
be in the best interest of the participant (eg, compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments.
35. Is an employee of the investigator or study site, with direct involvement in the proposed
study or other studies under the direction of that investigator or study site, as well as
family members of the employees or the investigator.