Inclusion Criteria: 

• Has had a diagnosis of CD at least 3 months before Randomization (confirmed by ileocolonoscopy + histology). For participants with no documented confirmation of CD diagnosis or if previous diagnosis is not deemed conclusive, CD diagnosis must be confirmed (by local pathology report) at time of screening ileocolonoscopy. Note that mention of “chronic inflammation” or “Crohn’s disease” or equivalent on pathology report is acceptable.
• Has moderately to severely active CD as defined by CDAI 220 – 450 at Baseline.
• Has SES-CD score (excluding the presence of narrowing component) ≥6 if ileocolonic or colonic disease; or ≥4 if isolated ileal disease only, as confirmed by a central reader.
• Average daily very soft or liquid SF ≥4 and/or average daily APS ≥2 at Baseline.
• Demonstrated inadequate response, loss of response, or intolerance to one or more of the following categories of drugs: oral locally acting steroids, systemic steroids, immunomodulators, biologic and/or small molecule advanced therapies. 
  • Inadequate response is defined as outlined below:
    • Oral locally acting steroids (eg, budesonide, beclomethasone):
      • Signs and symptoms of persistently active disease (in the opinion of the investigator) during or after a course of at least 4 weeks of treatment with budesonide ≥9 mg/day or equivalent or beclomethasone ≥5 mg/day OR
      • Inability to taper <6 mg/day of budesonide or <5 mg/day of beclomethasone within 3 months of starting therapy, or if relapse occurs within 3 months of stopping corticosteroids
    • IV or oral systemic steroids (eg, prednisone):
      • Signs and symptoms of persistently active disease (in the opinion of the investigator) during or after a course of oral prednisone ≥40 mg/day (or equivalent) for 4 weeks or intravenously for 1 week OR
      •  Inability to taper to <10 mg/day of prednisone or equivalent within 3 months of starting therapy, or if relapse occurs within 3 months of stopping corticosteroids
    • Immunomodulators:
      • Signs and symptoms of persistently active disease (in the opinion of the investigator) during or after a course of at least 12 weeks of treatment with one of more of the following:
        • AZA ≥2 mg/kg/day or a lower dose but with documentation of a therapeutic concentration of 6-TGN
        • 6-MP ≥1.0 mg/kg/day or a lower dose but with documentation of a therapeutic concentration of 6-TGN
        • MTX ≥25 mg/week subcutaneous or intramuscular
        • Note: Oral MTX use is allowed during the study, however prior or current use of oral MTX is not sufficient for inclusion into the study.
        • Tacrolimus for participants in Australia, China, Japan or Taiwan (documented trough level of ≥5 ng/mL)
        • Note: A lower dosage of 6-MP or AZA or tacrolimus is acceptable if local guidelines specify a different treatment regimen. 
    • Approved advanced therapy for CD:
      • Signs and symptoms of persistently active disease (in the opinion of the investigator) during or after one of more of the following:
        • At least one 6-week induction regimen of infliximab (≥ 5 mg/kg IV at Weeks 0, 2, and 6), OR
        • At least one 4-week induction regimen of adalimumab (one 160-mg SC dose at Week 0, followed by one 80-mg SC dose at Week 2 [or one 80-mg SC dose at Week 0, followed by one 40-mg SC dose at Week 2, in countries where this dosing regimen is approved]), OR
        • At least one 4-week induction regimen of certolizumab pegol (400 mg SC at Weeks 0, 2, and 4), OR
        • At least one 6-week induction regimen of vedolizumab (300 mg IV at Weeks 0, 2, and 6, OR ▪ At least one 8-week induction regimen of ustekinumab (260 mg [≤55 kg] or 390 mg [>55 to ≤85 kg] or 520 mg [>85 kg] IV, followed by 90 mg SC at Week 8), OR
        • At least one 8-week induction regimen of risankizumab 600 mg IV at Baseline, Week 4 and 8, OR
        • At least one 12-week induction regimen of upadacitinib 45 mg orally once daily for 12 weeks, OR
  •  Loss of response defined as: 
    • Steroids and immunomodulators:
      • Recurrence of signs and symptoms of active disease (per investigator discretion) after initial improvement despite continuing the medications for ≥ the required treatment duration using ≥ the required dosing regimens
    •  Approved advanced therapy for CD:
      • Recurrence of signs and symptoms of active disease (per investigator discretion) despite receiving ≥ the approved maintenance dosing regimen following initial clinical benefit after induction
  •  Intolerance defined as unable to achieve therapeutic doses or treatment durations because of dose limiting adverse effect. 
    • Demonstration of intolerance requires no minimum dose or duration of use (intolerance includes patients with a known TPMT genetic mutation or low activity). Note: Participants who discontinued biologics for reasons other than inadequate response as defined above or intolerance (eg, change of insurance) must meet the criteria for intolerance or inadequate response to oral locally acting steroids, systemic steroids (prednisone or equivalent), and/or immunomodulators as defined above. 
• Is an individual of any sex/gender from 16 years to 75 years of age inclusive, at the time of providing the informed consent (or assent if applicable). Note: Adolescent individuals ≥16 and <18 years of age who meet Tanner Stage 5 for development can participate in Study 1 or Study 2 if approved by the country or regulatory/health authority. If these approvals are not granted, only individuals ≥18 years of age can be eligible for these studies. 
  • Note: There are no contraceptive requirements for participants assigned male sex at birth.
• A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:
  • Is not a POCBP
  • OR Is a POCBP and:
    • Uses an acceptable contraceptive method or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), from at least 4 weeks prior to Day 1/Week 0, during the intervention period, and for at least 14 weeks after the last dose of study intervention
    • The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBP should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    • Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Additional requirements for pregnancy testing during and after study intervention.
    • Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.
• For participants ≥18 years of age: The participant (or legally acceptable representative) has provided documented informed consent for the study. The participant may also provide consent for FBR and/or the PK Subpopulation (Study 1 only). However, the participant may participate in the study without participating in FBR and/or the PK Subpopulation (Study 1 only).
• For participants ≥16 to <18 years of age: Has a legally acceptable representative who provided documented informed consent and the participant has provided documented informed assent. The legally acceptable representative may also provide documented informed consent and the participant may also provide documented informed assent for FBR and/or the PK Subpopulation (Study 1 only).

Exclusion Criteria:

• Has diagnosis of UC or indeterminate colitis (IBD undefined) or other types of colitis or enteritis that may confound efficacy assessment.
• Has CD isolated to the stomach, duodenum, jejunum, or perianal region, without colonic and/or ileal involvement.
• Currently has any of the following complications of CD:
  • Suspected or diagnosed with intra-abdominal or perianal abscess.
  • Known symptomatic stricture or colonic stenosis not passable in endoscopy (including pediatric colonoscope). Note: ileal stenosis or IC valve stenosis is not exclusionary.
  • Fulminant colitis
  • Toxic megacolon
  • Any other manifestation that might require surgery while enrolled in the study.
• Has current stoma or need for colostomy or ileostomy.
• Is missing>2 segments of the following 5 segments: terminal ileum, right colon, transverse colon, sigmoid and left colon, and rectum.
• Has been diagnosed with short gut or short bowel syndrome, or any other uncontrolled chronic diarrhea besides Crohn’s disease.
• Has surgical bowel resection within 3 months before screening.
• Has prior or current gastrointestinal dysplasia, other than completely removed low-grade dysplastic lesions in any biopsy performed during or before the Screening ileocolonoscopy.  Note: If the Screening ileocolonoscopy also served as a cancer surveillance for participants with colonic CD, dysplasia assessment will be done locally, and the results must be available before randomization.
• Has been hospitalized for the treatment of CD within 2 weeks before Screening.
• Has any infections requiring IV or intramuscular anti-infectives or hospitalization within 4 weeks prior to randomization
• Has infections requiring oral anti-infective treatment within 2 weeks prior to randomization (except latent TB requiring complete course of intervention during the study). Use of CD-related antibiotics is permitted.
• Has chronic infection requiring ongoing antimicrobial treatment (eg, chronic pyelonephritis, osteomyelitis, and bronchiectasis).
• Stool positive for pathogens (eg, Clostridioides difficile toxin, pathogenic Escherichia coli, Salmonella species, Shigella species, Campylobacter species, Yersinia species) as well as ova and parasites at Screening. Note: Participants who are positive for enteric pathogens at Screening, and who are considered screen failures, may be rescreened after complete resolution of the infection
• Has had a cytomegalovirus that resolved less than 4 weeks prior to Screening.
• Has a transplanted organ which requires continued immunosuppression.
• Has a history of cancer (except fully treated non-melanoma skin cell cancers or cervical carcinoma in situ after complete surgical removal) within the last 5 years or have had diagnostic evaluation suggestive of malignancy (eg, chest or breast imaging) in which the possibility of malignancy cannot be reasonably excluded following additional clinical assessments.
• Is known to be infected with HBV, HCV, or HIV.
  • Participants with positive HBsAg are excluded from the study. Participants with negative HBsAg and positive HBcAb must have further testing for HBV-DNA. Participants with HBV-DNA ≥LLOQ are not eligible for the study.Participants with HBV-DNA are eligible.
  • Participants with positive HCV Abs at Screening must have further testing for HCV RNA. Participants with HCV RNA detectable are not eligible for the study. Participants with positive HCV Abs but HCV RNA not detectable and successfully treated HCV with no recurrence for ≥1 year are eligible.
  • Participants with a history of HIV infection or have a positive HIV-1 or HIV-2 Ab test are not eligible for the study.
• Participant has active TB or meets TB exclusionary parameters (refer to Section 8.3.6.3 for specific requirements for TB testing).
• Has confirmed or suspected COVID-19 infection. Note: Participants with recent confirmed or suspected COVID-19 infection may participate under the following conditions: 
  • Participants with COVID-19 infection confirmed by a PCR or an antigen test:
    • For asymptomatic participants, randomization must be at least 10 days after the positive COVID-19 test.
    • For symptomatic participants, randomization must be at least 10 days after onset of symptoms and at least 3 days after resolution of fever without the use of fever-reducing medications, and the participant must have a clinically meaningful improvement in symptoms.
  • Participants with suspected COVID-19 infection:
    • For participants with signs/symptoms suggestive of COVID-19 infection, a molecular (ie, PCR) test must be performed to rule out COVID-19 infection before randomization. OR
    • Randomization must be at least 10 days after onset of symptoms and at least 3 days after resolution of fever without the use of fever-reducing medications, and the participant must have clinically meaningful improvement in symptoms.
• Has any history of clinically significant drug or alcohol abuse in the opinion of the Investigator within the last 6 months.
• Has had major surgery within 3 months before Screening or has a major surgery (i.e., surgical procedure requiring general anesthesia) planned during the study.
• Has a concurrent clinically significant disease or clinically relevant laboratory abnormalities, or a history of any illness or medical condition that, in the opinion of the investigator, might confound the results of the study or poses an additional risk to the participant by their participation in the study.
• Is receiving CD-related antibiotics and has not been on stable doses for at least 14 days before Baseline or has discontinued these medications within 14 days of Randomization.
• Is receiving oral aminosalicylates and has not been on stable doses for at least 14 days before Baseline or has discontinued these medications within 14 days of Randomization.
• Is receiving immunomodulators (AZA, 6-MP, MTX ≤15 mg/wk, Tacrolimus) and has not been on stable doses for at least 4 weeks before Baseline or has discontinued these medications within 4 weeks of Randomization.
• Is receiving oral corticosteroids at the following prohibited doses or has not been on a stable dose for ≥2 weeks prior to Randomization:
  • Budesonide >9 mg/day
  • Beclomethasone >5 mg/day
  • Prednisone or equivalent >20 mg/day
• Is currently receiving or is planning to receive total parenteral nutrition at any time during study treatment.
• Has received prohibited medications within the specified timeframes before randomization. These medications are also prohibited during the study. 
• Has received fecal microbial transplantation within 4 weeks before randomization.
• Prior exposure to tulisokibart (MK-7240, PRA023) or another anti-TL1A Ab.
• Has participated in another investigational clinical study within 8 weeks or 5 half-lives of the investigational drug (whichever is longer) before randomization. This window will be derived from the date of the last dose of study medication taken in the previous study. Participants enrolled in observational/non-interventional studies may be included.
• Has screening laboratory test results with the following values:
  • Hemoglobin <8.0 g/dL (80 g/L)
  • WBC <2500/mm (3.5 × 10 /L)
  • Absolute neutrophil count <1000/mm (1 × 10 /L)
  • Absolute lymphocyte count <500/mm (0.5 × 10 /L)
  • Platelets <100,000/mm (100 × 10 /L)
  • ALT or AST >2.0 × ULN
  • Total bilirubin ≥ 2 mg/dL, except for individuals with isolated elevation of indirect bilirubin relating to Gilbert syndrome 
• Has known allergies, hypersensitivity, or intolerance to tulisokibart or its excipients. Note: Refer to the IB for details regarding excipients for tulisokibart.
• Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 5/8/2024. Questions regarding updates should be directed to the study team contact.