1. Man or woman (according to their reproductive organs and functions assigned by chromosomal complement) of ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place).
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 ≥4, based on the unweighted CDAI component of the
number of liquid or very soft stools
OR
b. Mean daily AP score ≥2, based on the unweighted CDAI component of AP
4. Have endoscopic evidence of active ileocolonic Crohn’s disease as assessed by central endoscopy reading at the screening endoscopy (SoA [Section 1.3]) defined as a screening SES-CD score ≥6 (or ≥4 for participants with isolated ileal disease), based on the presence of ulceration in at least 1 of the 5 ileocolonic segments, resulting in the following specified ulceration component scores:
a. A minimum score of 1 for the component of “size of ulcers”
AND
b. A minimum score of 1 for the component of “ulcerated surface”
5. A participant who has had extensive colitis for ≥8 years, or disease limited to a segment of the colon for ≥10 years, must:
a. Have had a full colonoscopy to assess for the presence of dysplasia within 1 year before the first dose of study intervention
OR
b. Has a full colonoscopy with biopsy surveillance for dysplasia as the baseline endoscopy during the screening period. Results from these surveillance biopsies must be negative for dysplasia (low-grade, high-grade, or “indefinite dysplasia in reactive atypia”) prior to the first dose of study intervention
Tuberculosis
9. A potential participant is considered eligible if the participant meets all of the following TB screening criteria:
Note: Interferon gamma release assay (IGRA) testing includes either QuantiFERON-TB® or T-SPOT®.TB.
a. Have no history of active TB or show signs or symptoms suggestive of active, TB upon medical history and/or physical examination at screening.
b. Have no history of latent 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:
1) Currently receiving treatment for latent TB
OR
2) Will initiate treatment for latent TB prior to the first administration of study intervention
c. Have had no recent close contact with a person with active TB. If there has been contact, such participants are referred to a physician specializing in TB to determine if treatment is warranted or not. This evaluation must be adequately documented and, if treatment is recommended, the participant must be receiving appropriate treatment prior to the first administration of study intervention.
d. Have a negative IGRA test result within 2 months prior to the first administration of study intervention, or who:
o Have a history of adequately treated latent TB described above.
o Have a newly identified positive IGRA test result in which active TB has been ruled out and for which appropriate treatment for latent TB has been initiated prior to the first administration of study intervention.
o Have a false-positive IGRA test as determined by the following:
A suspected false-positive initial IGRA test must be repeated. If repeat testing is NOT positive, the participant must be referred to a physician specializing in TB to determine if the initial test can be considered a false-positive. This evaluation must be adequately documented prior to the first administration of study intervention. If repeat testing is positive, however, it will be considered a true-positive and the participant is only eligible if active TB has been ruled out and appropriate treatment for latent TB has been initiated as described
above.
e. Have a chest radiograph (both posterior-anterior and lateral views, or per local/country regulations where applicable), or chest computed tomography (CT) within 3 months prior to the first administration of study intervention that shows no abnormalities suggestive of active or inactive TB.
Contraception
10. A woman of childbearing potential must have a negative serum pregnancy test result at screening.
11. Before randomization, a woman must be (as defined in Appendix 7 [Section 10.7])
a. Not of childbearing potential (refer to Section 10.7 for instances when a screening follicle stimulating hormone (FSH)test should be considered)
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 –the end of relevant systemic exposure. Note: The method selected must meet local/regional regulations/guidelines for highly effective contraception.
12. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 12 weeks after the last administration of study intervention.
13. During the study and for at least 12 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 (ie, condom with spermicidal foam/gel/film/cream/suppository or female condom/occlusive cap [diaphragm or cervical/vault caps] with spermicidal foal/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
14. Each participant 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.
16. Be willing and able to adhere to all specified requirements, including but not limited to completion of assessments, adherence to visit schedule, and compliance with the lifestyle restrictions.
5.2. Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
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.
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 24 weeks, or any other intra-abdominal or other major surgery within 12 weeks, before first dose of study intervention.
4. Has a draining (ie, functioning) stoma or ostomy.
5. Presence on screening endoscopy of adenomatous colonic polyps, if not removed before study entry, or history of adenomatous colonic polyps that were not removed.
6. Has a stool culture or other examination positive for an enteric pathogen, including Clostridioides difficile (formerly known as 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.
Concomitant or Previous Medical Therapies Received
7. 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 received within 4 weeks of baseline
d. Biologic agents:
1) Anti-TNFα therapy (eg, infliximab, etanercept, certolizumab pegol, adalimumab, golimumab) received within 8 weeks of baseline
2) Vedolizumab received within 12 weeks of baseline
3) Other immunomodulatory biologic agents, including approved and investigational 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 half-lives of baseline, whichever is longer. (Refer to exclusion criterion 7.d.3 for investigational biologic agents).
f. Non-autologous 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.
8. Has previously received a biologic agent targeting IL-12/23 or IL-23, including but not limited to ustekinumab, briakinumab, brazikumab, guselkumab, mirikizumab, and mrisankizumab.
Infections or Predisposition to Infections:
9. Has a history of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, before screening. Participants with radiographic evidence of possible prior histoplasmosis or coccidioidomycosis will be excluded.
10. Has a history of, or ongoing, chronic or recurrent infectious disease, including but not limited to, sinopulmonary infections, bronchiectasis, recurrent renal/urinary tract infections (eg, pyelonephritis, cystitis), an open, draining, or infected skin wound, or an ulcer.
11. Chest radiograph must be obtained within 12 weeks before the first dose of study intervention. Results that shows an abnormality suggestive of an undiagnosed pulmonary pathology including but not limited to a malignancy, a previously unrecognized pulmonary pathology, as well as active or latent infections from TB, histoplasmosis, or coccidiomycosis would be exclusionary. A chest CT scan obtained outside of the protocol instead of a chest radiograph is also acceptable. Refer to inclusion criteria 9 for information regarding eligibility with a history of latent TB.
12. History of human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV at screening.
13. Is seropositive for antibodies to hepatitis C virus (HCV), unless they satisfy one of the following conditions:
a. Has a history of successful treatment, defined as being negative for HCV RNA at least 12 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 12 weeks prior to screening and a negative HCV RNA test result at screening.
14. Tests positive for hepatitis B virus (HBV) infection (Appendix 4[Section 10.4]).
15. Bacille Calmette-Guérin (BCG) vaccination within 12 months or any other live bacterial or live viral vaccination within 4 weeks prior to screening, or plans to receive such vaccines during the study.
16. Has or has had a nontuberculous mycobacterial infection or clinically significant opportunistic infection (eg, cytomegalovirus colitis, pneumocystosis, invasive
aspergillosis).
17. Has had a clinically significant infection (ie, hepatitis, sepsis, pneumonia, or pyelonephritis), has been hospitalized for an infection, or has been treated with
parenteral antibiotics for an infection within 8 weeks 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 (ie, acute upper respiratory tract infection, uncomplicated urinary tract infection).
18. Has current signs or symptoms of a clinically significant infection. Ongoing infections not considered clinically significant at the discretion of the investigator need not be exclusionary (ie, acute upper respiratory tract infection, uncomplicated urinary tract infection).
19. Has evidence of a herpes zoster infection within 8 weeks before the first dose of study
intervention.
20. During the 6 weeks prior to baseline, have had ANY of (a) confirmed severe acute mrespiratory syndrome coronavirus-2 (SARS-CoV-2) (Coronavirus Disease 2019
[COVID-19]) infection (test positive), OR (b) suspected SARS-CoV-2 infection (clinical features without documented test results), OR (c) close contact with a person with known or suspected SARS-CoV-2 infection
Exception: May be included with a documented negative result for a validated SARS-CoV-2 test
a. Obtained at least 2 weeks after conditions (a), (b), (c) above (timed from resolution of key clinical features ifpresent, eg, fever, cough, dyspnea)
AND
b. With absence of ALL conditions (a), (b), (c) above during the period between the negative test result and the baseline study visit
Malignancy or Increased Potential for Malignancy:
21. 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).
22. Has a known 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
23. Has a history of severe, progressive, or uncontrolled renal, genitourinary, hematologic, endocrine, cardiac, vascular, pulmonary, rheumatologic, neurologic, psychiatric, or metabolic disturbances, or signs and symptoms thereof.
24. Has a transplanted organ (with exception of a corneal transplant >12 weeks before screening).
25. Poor tolerability of venipuncture or lacks adequate venous access for required blood sample collections during the study period.
26. History of drug or alcohol abuse according to Diagnostic and Statistical Manual of Disorders (5th edition) criteria within 1 year before screening.
27. 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 non-suicidal self-injurious behavior who are determined to be at risk by the investigator may not be randomized.
28. Has known allergy, hypersensitivity, or intolerance to guselkumab or its excipients
29. 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.
30. 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
31. Currently participating or intends to participate in any other study using an
investigational agent or procedure during the conduct of this study.
32. 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.
33. 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.