Moderately to Severely Active Crohn's Disease

Phase 2 Dose-Ranging Study (GALAXI 1)  Primary Objectives  To evaluate the clinical efficacy of guselkumab in participants with Crohn’s disease  To evaluate the safety of guselkumab  Secondary Objectives  To evaluate the dose-response of guselkumab to inform dose selection for the Phase 3 portion of this protocol  To evaluate the efficacy of guselkumab on endoscopic improvement  To evaluate the pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of guselkumab therapy, including changes in C-reactive protein (CRP) and fecal calprotectin  Other Objectives  To evaluate the impact of guselkumab on health-related quality of life (HRQOL) and health economics outcome measures  To evaluate the efficacy of guselkumab on histologic improvement  To evaluate the impact of treatment with guselkumab on intestinal mucosal gene expression profiles and cellular composition associated with Crohn’s disease Phase 3 Dose-Confirming Studies (GALAXI 2 and GALAXI 3)  Primary Objectives  To evaluate the clinical efficacy of guselkumab in participants with Crohn’s disease  To evaluate the safety of guselkumab  Secondary Objectives  To evaluate the efficacy of guselkumab on endoscopic improvement  To evaluate the impact of guselkumab on HRQOL  To evaluate the PK, immunogenicity, and PD of guselkumab therapy, including changes in CRP and fecal calprotectin  Other Objectives  To evaluate the impact of guselkumab on health economics outcome measures  To evaluate the efficacy of guselkumab on histologic improvement  To evaluate the impact of treatment with guselkumab on intestinal mucosal gene expression profiles and cellular composition associated with Crohn’s disease

guselkumab

guselkumab

single-dose prefilled syringe

100 mg
200 mg
400 mg
placebo

Phase 2 Dose-Ranging Study (GALAXI 1)
Primary Endpoint
Change from baseline in the CDAI score at Week 12.
Major Secondary Endpoints
• Clinical remission at Week 12 (defined as CDAI score <150).
• Clinical response at Week 12 (defined as ≥100-point reduction from baseline in CDAI score
or CDAI score <150).
• PRO-2 remission at Week 12 (defined as an abdominal pain [AP] mean daily score at or
below 1 AND stool frequency [SF] mean daily score at or below 3, ie, AP≤1 and SF≤3).
• Clinical-biomarker response at Week 12 (clinical response based on CDAI score and ≥50%
reduction from baseline in CRP or fecal calprotectin).
• Endoscopic response at Week 12 (defined as at least 50% improvement from baseline in the
Simple Endoscopic Score for Crohn’s Disease [SES-CD] or SES-CD score ≤2)

Phase 3 Dose-Confirming Studies (GALAXI 2 and GALAXI 3)
Primary Endpoint
The primary endpoint is clinical remission at Week 12 (defined as CDAI score <150). For this
endpoint, comparisons of each guselkumab group with placebo will be made.
Major Secondary Endpoints
The major secondary endpoints are described below. Note that the final ordering of the major
secondary endpoints will be determined after the Phase 2 data have been evaluated and the
Phase 3 testing procedure has been determined; this ordering will be provided in the
Phase 3 Statistical Analysis Plan (SAP).
• Clinical remission at Week 48 (defined as CDAI < 150)
• Durable clinical remission at Week 48 (defined as CDAI<150 for ≥80% of all visits between
Week 12 and Week 48 [ie, at least 8 of 10 visits], which must include Week 48)
• Corticosteroid-free clinical remission at Week 48 (defined as CDAI score <150 at Week 48
and not receiving corticosteroids at Week 48)
• PRO-2 remission at Week 12 (defined as an AP mean daily score at or below 1 AND SF
mean daily score at or below 3, ie, AP≤1 and SF≤3)
• PRO-2 remission at Week 48
• Endoscopic response at Week 12 (defined as at least 50% improvement from baseline in
SES-CD score or SES-CD score ≤2)
• Endoscopic response at Week 48
• Fatigue response at Week 12 (based on the PROMIS Fatigue Short Form 7a; to be defined in
the SAP)

Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the protocol:
1. Be male or female (according to their reproductive organs and functions assigned by
chromosomal complement) ≥18 years of age.
2. Have Crohn’s disease or fistulizing Crohn’s disease of at least 3 months duration (defined as
a minimum of 12 weeks), with colitis, ileitis, or ileocolitis, confirmed at any time in the past
by radiography, histology, and/or endoscopy.
3. Have clinically active Crohn’s disease, defined as a baseline CDAI score ≥220 but ≤450 and
either:
a. Mean daily SF count >3, based on the unweighted CDAI component of the number of
liquid or very soft stools
OR
b. Mean daily AP score >1, based on the unweighted CDAI component of abdominal pain
4. Have endoscopic evidence of active ileocolonic Crohn’s disease as assessed by central
endoscopy reading at the screening endoscopy, defined as a screening SES-CD score ≥3,
which indicates the presence of at least 1 large ulcer (in the ileum, colon, or both) that
results in:
a. a minimum score of 2 for the component of “size of ulcers”
AND
b. a minimum score of 1 for the component of “ulcerated surface”.
Within each of the studies, a maximum of 10% of the total enrolled population will be
participants who have baseline scores for SES-CD <4 (ie, for participants with isolated ileal
disease) or SES-CD <7 (ie, for participants with colonic or ileocolonic disease).
Concomitant or previous medical therapies received
5. Prior or current medication for Crohn’s disease must include at least 1 of the following, and
must fulfill additional criteria as described in Appendix 2 (Section 10.2), Appendix 3
(Section 10.3), and Appendix 4 (Section 10.4):
a. Current treatment with oral corticosteroids (including budesonide and beclomethasone
dipropionate) and/or immunomodulators (AZA, 6-MP, MTX)
OR
b. History of failure to respond to, or tolerate, at least 1 of the following therapies: oral
corticosteroids (including budesonide and beclomethasone dipropionate) or
immunomodulators (AZA, 6-MP, MTX).
OR
c. History of corticosteroid dependence (ie, an inability to successfully taper
corticosteroids without a return of the symptoms of Crohn’s disease).
OR
d. Has previously demonstrated lack of initial response (ie, primary nonresponders),
responded initially but then lost response with continued therapy (ie, secondary
nonresponders), or were intolerant to 1 or more biologic agents at a dose approved for
the treatment of Crohn's disease (ie, infliximab, adalimumab, certolizumab pegol,
vedolizumab, or approved biosimilars for these agents).
Note: Participants meeting criteria 5a-c may also be naïve to biologic therapy (ie, a TNF
antagonist or vedolizumab or ustekinumab) or may have been exposed to these biologic
therapies but have not demonstrated inadequate response or intolerance. Participants with
prior exposure to IL-12/23 or IL-23 agents are ineligible for entry into this protocol, with the
exception of participants who have had limited exposure to ustekinumab at its approved
labeled dosage AND have met the required wash-out criterion AND have not demonstrated
failure or intolerance to ustekinumab (per Exclusion Criterion 7, Appendix 4
[Section 10.4]).
6. Adhere to the following requirements for concomitant medication for the treatment of
Crohn's disease. The following medications are permitted provided that doses meeting the
requirements listed below are stable or have been discontinued prior to baseline within the
timeframes specified below:
a. Oral 5-aminosalicylic acid (5-ASA) compounds on stable doses for at least 2 weeks; or
if recently discontinued, must have been stopped for at least 2 weeks.
b. Oral corticosteroids at a prednisone-equivalent dose at or below 40 mg/day, or 9 mg/day
of budesonide, or 5 mg/day beclomethasone dipropionate, and on stable dosing for at
least 2 weeks; or if recently discontinued, must have been stopped for at least 2 weeks.
c. Conventional immunomodulators (ie, AZA, 6-MP, or MTX) for at least 12 weeks and
have been on a stable dose for at least 4 weeks; or if recently discontinued, must have
been stopped for at least 4 weeks.
d. If receiving antibiotics as a primary treatment of Crohn's disease, doses must be stable
for at least 3 weeks; or if recently discontinued, must have been stopped for at least
3 weeks.
e. If receiving enteral nutrition as a primary treatment for Crohn’s disease, must have been
receiving for at least 2 weeks; or if recently discontinued, must have been stopped for at
least 2 weeks.
Screening laboratory tests
7. Have 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 5-week screening period:
a. Hemoglobin ≥8.0 g/dL.
b. White blood cells (WBCs) ≥3.5 x 10
3
/µL.
c. Neutrophils ≥1.5 x 10
3
/µL.
d. Platelets ≥100 x 10
3
/µL.
e. Serum creatinine ≤1.5 mg/dL.
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations
must be ≤2 times the upper limit of normal (ULN) range for the laboratory conducting
the test.
g. Direct (conjugated) bilirubin <1.0 mg/dL.
Tuberculosis
8. Are considered eligible according to the following tuberculosis (TB) screening criteria:
a. Have no history of latent or active TB prior to screening. An exception is made for
participants who have a history of latent TB AND who satisfy one of the following
criteria:
o currently receiving treatment for latent TB
o will initiate treatment for latent TB prior to or simultaneously with the first
administration of study intervention
OR
o have documentation of having completed appropriate treatment for latent TB
within 5 years prior to the first administration of study intervention. It is the
responsibility of the investigator to verify the adequacy of previous antituberculous treatment and provide appropriate documentation.
b. Have no signs or symptoms suggestive of active TB upon medical history and/or
physical examination.
c. Have 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 prior to or
simultaneously with the first administration of study intervention.
d. Within 8 weeks prior to the first administration of study intervention, have a negative
QuantiFERON®-TB Gold test result, or have a newly identified positive
QuantiFERON-TB Gold test in which active TB has been ruled out and for which
appropriate treatment for latent TB has been initiated either prior to or simultaneously
with the first study intervention administration (see Section 8.2.6 and Appendix 5
[Section 10.5]). Indeterminate results should be handled as outlined in Section 8.2.6.
Note: A negative tuberculin skin test result (see Appendix 6 [Section 10.6]) is
additionally required if the QuantiFERON-TB Gold test is not approved/registered in
the country in which this protocol is being conducted. In Ukraine, while the
QuantiFERON-TB gold test is not approved/registered, it is acceptable, and an
additional tuberculin skin test is not required. The QuantiFERON-TB Gold 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 8a.
e. Have a chest radiograph (both posterior-anterior and lateral views, or per country
regulations where applicable), taken ≤12 weeks before the first administration of study
intervention and read by a qualified radiologist, with no evidence of current, active TB
or old, inactive TB.
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.
9. A female participant of childbearing potential must have a negative urine pregnancy test
result at screening and baseline.
10. Before randomization, a female participant must be (as defined in Appendix 7
[Section 10.7], Contraceptive and Barrier Guidance and Collection of Pregnancy
Information):
a. Not of childbearing potential
b. Of childbearing potential and:
o 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 16 weeks after last dose (ie, the
end of relevant systemic exposure). Examples of highly effective methods of
contraception are located in Appendix 7 (Section 10.7), 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 throughout the inclusion and exclusion
criteria.
11. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for a period of 16 weeks after the last administration of
study intervention.
12. During the study and for at least 16 weeks after the last administration of study intervention,
a male participant
a. who is sexually active with a female of childbearing potential must agree to use a
barrier method of contraception (eg, condom with spermicidal
foam/gel/film/cream/suppository).
b. who is sexually active with a pregnant female must use a condom.
c. must agree not to donate sperm for the purpose of reproduction.
General
13. Be willing and able to adhere to the lifestyle restrictions (Section 5.3) specified in this
protocol.
14. Must sign an informed consent form (ICF) indicating that he or she understands the purpose
of, and procedures required for, the study and is willing to participate in the study.
15. Must sign a separate ICF if he or she agrees to provide an optional DNA sample for research
(where local regulations permit). Refusal to give consent for the optional DNA research
sample does not exclude a participant from participation in the study.

Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the protocol:
1. Has complications of Crohn’s disease, such as symptomatic strictures or stenoses, short gut
syndrome, or any other manifestation, that might be anticipated to require surgery, could
preclude the use of the CDAI to assess response to therapy, or would possibly confound the
ability to assess the effect of treatment with guselkumab or ustekinumab.
2. Currently has or is suspected to have an abscess. Recent cutaneous and perianal abscesses
are not exclusionary if drained and adequately treated at least 3 weeks before baseline, or
8 weeks before baseline for intra-abdominal abscesses, provided that there is no anticipated
need for any further surgery. Participants with active fistulas may be included if there is no
anticipation of a need for surgery and no abscesses are currently identified.
3. Has had any kind of bowel resection within 6 months, or any other intra-abdominal or other
major surgery (eg, requiring general anesthesia) within 12 weeks, before baseline.
4. Has a draining (ie, functioning) stoma or ostomy.
5. Has a stool culture or other examination positive for an enteric pathogen, including
Clostridium difficile toxin, in the previous 4 months, unless a repeat examination is negative
and there are no signs of ongoing infection with that pathogen.
Concomitant or previous medical therapies received
6. Has received any of the following prescribed medications or therapies within the specified
period:
a. IV corticosteroids received within 3 weeks of baseline
b. Cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil received within 8 weeks
of baseline
c. 6-thioguanine (6-TG) received within 4 weeks of baseline
d. Biologic agents:
1) Anti-TNF therapy (eg, infliximab, etanercept, certolizumab pegol, adalimumab,
golimumab) received within 8 weeks of baseline
2) Vedolizumab received within 16 weeks of baseline
3) Ustekinumab received within 16 weeks of baseline
4) Other immunomodulatory biologic agents received within 12 weeks of baseline or
within 5 half-lives of baseline, whichever is longer.
e. Any investigational intervention received within 4 weeks of baseline or within 5 halflives of baseline, whichever is longer.
f. Nonautologous stem cell therapy (eg, Prochymal), natalizumab, efalizumab, or biologic
agents that deplete B- or T-cells (eg, rituximab, alemtuzumab, or visilizumab) received
within 12 months of baseline.
g. Treatment with apheresis (eg, Adacolumn apheresis) or total parenteral nutrition for
Crohn’s disease within 3 weeks of baseline.
7. Has previously received a biologic agent targeting IL-12/23 or IL-23, including but not
limited to briakinumab, brazikumab, guselkumab, mirakizumab (formerly LY2525623), and
risankizumab.
Exception: Participants who have had limited exposure to ustekinumab at its approved
labeled dosage AND have met the required wash-out criterion AND have not demonstrated
failure or intolerance to ustekinumab (criteria specified in Appendix 4 [Section 10.4]) are
not excluded from this protocol provided that other inclusion criteria have been satisfied and
no other exclusion criteria are met.
Infections or predisposition to infections:
8. Has a history of, or ongoing, chronic or recurrent infectious disease, including but not
limited to, chronic renal infection, chronic chest infection (eg, bronchiectasis), recurrent
urinary tract infection (eg, recurrent pyelonephritis or chronic nonremitting cystitis), or
open, draining, or infected skin wounds or ulcers.
9. Has current signs or symptoms of a clinically significant infection. Established non-serious
infections (eg, acute upper respiratory tract infection, simple urinary tract infection) need not
be considered exclusionary at the discretion of the investigator.
10. Has a history of serious infection (eg, hepatitis, sepsis, pneumonia, or pyelonephritis),
including any infection requiring hospitalization or IV antibiotics, for 8 weeks before
baseline.
11. Has evidence of a herpes zoster infection within 8 weeks before baseline.
12. Has a history of latent or active granulomatous infection, including histoplasmosis or
coccidioidomycosis, prior to screening. Participants with radiographic evidence of possible
prior histoplasmosis or coccidioidomycosis will be excluded.
13. Has a chest radiograph within 12 weeks prior to the first administration of study intervention
that shows an abnormality suggestive of a malignancy or current active infection, including
TB.
14. Has or has had a nontuberculous mycobacterial infection or clinically significant
opportunistic infection (eg, cytomegalovirus colitis, pneumocystosis, invasive aspergillosis).
15. Participants must undergo screening for human immunodeficiency virus (HIV). Any
participant who has a history of HIV antibody positivity, or tests positive for HIV at
screening, is not eligible for this study.
16. Participants who are seropositive for antibodies to hepatitis C virus (HCV), unless they have
2 negative HCV RNA test results at least 6 months apart after completing antiviral treatment
and prior to screening, and have a third negative HCV RNA test result at screening.
17. Tests positive for hepatitis B virus (HBV) infection (Appendix 8 [Section 10.8]).
Note: For participants who are not eligible for this study due to HIV, HCV, HBV, or TB test
results, consultation with a physician with expertise in the treatment of those infections is
recommended.
18. Has received, or is expected to receive, any live virus or bacterial vaccination within
12 weeks before the first administration of study intervention. For Bacille Calmette-Guérin
(BCG) vaccine, see Exclusion Criterion 14.
19. Has had a BCG vaccination within 12 months of screening.
Malignancy or increased potential for malignancy
20. 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 study intervention administration or cervical carcinoma in situ that has been treated
with no evidence of recurrence for at least 3 months before the first study intervention
administration).
21. Has a known history of lymphoproliferative disease, including monoclonal gammopathy of
unknown significance, lymphoma, or signs and symptoms suggestive of possible
lymphoproliferative disease, such as lymphadenopathy, hepatomegaly, or splenomegaly, or
monoclonal gammopathy of undetermined significance.
Coexisting medical conditions or past medical history
22. Has a 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.
23. Has a transplanted organ (with exception of a corneal transplant >12 weeks before
screening).
24. Is unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack
of adequate venous access.
25. Is known to have had a history of drug or alcohol abuse according to Diagnostic and
Statistical Manual of Disorders (5th edition) (DSM-V) criteria within 12 months before
baseline.
26. Has 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 nonsuicidal self-injurious behavior who are determined to be at risk by the investigator may not
be randomized.
27. Has known allergies, hypersensitivity, or intolerance to guselkumab or ustekinumab or any
of their excipients (see guselkumab IB and ustekinumab IB).
28. Is a woman who is pregnant, or breastfeeding, or planning to become pregnant while
enrolled in this study or within 16 weeks after the last administration of study intervention.
29. Is a man who plans to father a child while enrolled in this study or within 16 weeks after the
last administration of study intervention.
General
30. Is currently enrolled in or intends to participate in any other study using an investigational
agent or procedure during participation in this study.
31. 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.
32. 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.