Clinical Trials

Inclusion Criteria:

• Be male or female (according to their reproductive organs and functions assigned by chromosomal complement) ≥ 18 years of age.
• Has CD or fistulizing CD of at least 3 months’ duration, with colitis, ileitis, or ileocolitis, confirmed at some time in the past by radiography, histology, and/or endoscopy.
• Has moderately-to-severely active CD with a baseline CDAI score of ≥ 220 and ≤ 450.
• Has one or more ulceration on screening ileocolonoscopy (which, by definition, would result in an SES-CD of at least 3).
  • Note: If a subject had an ileocolonoscopy but then screen failed for another reason, if he/she is rescreened within 3 months, then that ileocolonoscopy is sufficient for inclusion if all other entry criteria are met.
• Meets the following requirements for prior or current medications for CD:
  • Has failed conventional therapy:
    • Is currently receiving corticosteroids and/or immunomodulators (i.e., AZA, MTX, or 6-MP) at adequate therapeutic doses; OR
    • Has a history of failure to respond to, or tolerate, an adequate course of corticosteroids and/or immunomodulators (i.e., AZA, MTX, or 6-MP); OR
    • Is corticosteroid dependent or has a history of corticosteroid dependency; AND
  • Has not previously received an approved biologic for CD (i.e., infliximab, adalimumab, certolizumab pegol, ustekinumab, natalizumab, vedolizumab or approved biosimilars of these agents).
• Subjects on oral corticosteroids (e.g., prednisone, budesonide) at a prednisone-equivalent dose of ≤ 40 mg/day or ≤ 9 mg/day of budesonide are permitted provided doses meeting these requirements are stable for 3 weeks prior to baseline (Week 0) or these have been discontinued at least 3 weeks prior to baseline.
• Subjects on the immunomodulators AZA, 6-MP, or MTX at screening (or recently prior), must discontinue these medications at least 3 weeks prior to baseline.
• Has screening laboratory test results within the following parameters:
  • Hemoglobin: ≥ 8.5 g/dL
  • White blood cells (WBC): > 3.5 x 103/μL
  • Neutrophils: >1.5 x 103/μL
  • Platelets: > 100 x 103/μL
  • Serum creatinine: < 1.7 mg/dL
  • Aspartate transaminase (AST) and alanine transaminase (ALT) concentrations:
    • Within 2 times the upper limit of normal range for the laboratory conducting the test.
  • Direct (conjugated) bilirubin: < 1.0 mg/dL.
• Is considered eligible per the following tuberculosis (TB) screening criteria:
  • Has no history of latent or active TB prior to screening; exceptions are made for a subject who:
    • Is currently receiving treatment for latent TB without evidence of active TB (or has initiated treatment for latent TB prior to Week 0 study agent administration);
    • Has a history of latent TB and documentation of having completed adequate treatment for latent TB within 5 years prior to the first administration of study agent.  It is the responsibility of the investigator to verify the adequacy of previous TB treatment and provide/obtain appropriate documentation.
  • Has no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
  • Has had no recent, known close contact with a person with active TB or, if there has been such contact, the subject is to 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 agent.
  • Within 2 months prior to the first administration of study agent, either has:
    • A negative QuantiFERON-TB test; or
    • A newly identified positive QuantiFERON-TB 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 administration of study agent.
    • A subject whose first QuantiFERON-TB test result is indeterminate should have the test repeated. In the event that additional QuantiFERON-TB test result is persistently indeterminate, the subject should also initiate treatment for latent TB in order to enter the study.
    • The QuantiFERON-TB In-Tube test is not required at screening for subjects with a history of latent TB and appropriate treatment as described above.
  • Has a chest radiograph (at least a posterior-anterior view), taken within 3 months prior to the first administration of study agent and read by a qualified radiologist, with no evidence of current, active TB or old, inactive TB.
• If a woman, before randomization she must be:
  • Postmenopausal, defined as:
    • ≥ 45 years of age with amenorrhea for at least 18 months; OR
    • ≥ 45 years of age with amenorrhea for at least 6 months and a serum FSH level > 40 IU/mL; OR
  • Of childbearing potential, in which case she must satisfy at least one of the below:
    • Surgically sterile (has had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), or
    • If heterosexually active, practicing a highly effective method of birth control, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method (e.g., condoms, diaphragm, or cervical cap, with spermicidal foam, cream, film, gel or suppository), or male partner sterilization, consistent with local regulations regarding use of birth control methods for subjects participating in clinical trials, for a period of 16 weeks after the last administration of study agent; or
    • Not heterosexually active.
  • Note: If a woman participant’s childbearing potential changes after start of the study (e.g., a premenarchal woman experiences menarche) or if women of childbearing potential who are not heterosexually active at screening become heterosexually active, they must agree to utilize a highly effective method of birth control, as described above.
• Female participants of childbearing potential (menstrual and not surgically sterile), must have a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test at screening and a negative urine pregnancy test at Week 0 (prior to randomization) and 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 agent.
• Male participants who are not surgically sterilized and are heterosexually active with a woman of childbearing potential, must agree to use a barrier method of contraception, consistent with local regulations, (e.g., condom with spermicidal foam/gel/film/cream/ suppository) and to not donate sperm during the study and for 16 weeks after last receiving study agent.
  • Note that barrier methods must also be used in all male subjects sexually active with pregnant partners for at least 16 weeks after last study agent administration.
• Sign an informed consent document indicating that he/she understands the purpose of, and procedures required for, the study and are willing to participate in the study.

Exclusion Criteria:

• Has complications of CD that are likely to require surgery or would confound the ability to assess the effect of ustekinumab or adalimumab treatment using the CDAI, such as: active stoma; short-gut syndrome and severe or symptomatic strictures or stenosis.
• 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 prior to baseline, or 8 weeks prior for intra-abdominal abscesses, if there is no anticipated need for any further surgery. Subjects with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses present.
• Has had any kind of bowel resection within 6 months prior to baseline or other intraabdominal surgery or a hospital admission for bowel obstruction within 3 months prior to baseline.
• At any time received any monoclonal antibody (including biosimilars) targeting TNFα, IL-12, or IL-23, or anti-integrin agents approved for CD (i.e., vedolizumab or natalizumab) or has received any of the following medications or therapies within the specified periods prior to baseline:
  • Any other investigational agent for CD (eg other biologics, small molecules or antisense RNA such as mongersen), unless at least 3 months or 5 half-lives have elapsed since last dose.
  • IV corticosteroids as a treatment for CD < 3 weeks prior to baseline.
  • Oral immunomodulatory agents other than AZA, 6-MP, or MTX (e.g., Janus kinase [JAK] inhibitors, 6-thioguanine [6-TG], cyclosporine, tacrolimus, sirolimus, tofacitinib, or mycophenolate mofetil) < 4 weeks prior to baseline.
    • Note that per inclusion criterion 7, typical immunomodulator agents [AZA, 6-MP or MTX] must have been discontinued at least 3 weeks prior to baseline.
  • Treatment with apheresis (e.g., Adacolumn apheresis) or total parenteral nutrition (TPN) as a treatment for CD < 3 weeks prior to baseline.
• Has a stool culture or other examination positive for an enteric pathogen, including Clostridium difficile toxin, in the last 4 months unless a repeat examination is negative and there are no signs of ongoing infection with that pathogen.
• Has received a Bacillus Calmette–Guérin (BCG) vaccination within 12 months or any other live bacterial or live viral vaccination within 2 weeks of baseline.
• Has a history of, or ongoing, chronic or recurrent infectious disease, including but not limited to, chronic renal infection, chronic chest infection, recurrent urinary tract infection (eg, recurrent pyelonephritis or chronic nonremitting cystitis), or infected skin wounds or ulcers.
• Has current signs or symptoms of infection, or recent (within 8 weeks prior to baseline) history of herpes zoster or serious infection (including any requiring hospitalization).  Established nonserious infections (e.g., acute upper respiratory tract infection, simple urinary tract infection) need not be considered exclusionary at the discretion of the investigator.
• Has evidence of current active infection, including TB, or a nodule suspicious for lung malignancy on screening or any other available chest radiograph, unless definitively resolved surgically or by additional imaging and with source document confirmation.
• Has a history of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, prior to screening. Refer to inclusion criteria for information regarding eligibility with a history of latent TB.
• Has ever had a nontuberculous mycobacterial infection or serious opportunistic infection (eg, cytomegalovirus causing colitis, Pneumocystis jiroveci, aspergillosis).
• Is seropositive for antibodies to hepatitis C (HCV) without a history of clearance or successful treatment, defined as being negative for HCV RNA in the past year and, if treated, at least 24 weeks after completing antiviral treatment. Subjects who test positive for anti-HCV antibodies must undergo further testing for HCV RNA. If the HCV RNA test is positive, the subject is not eligible for this study. If the HCV RNA test is negative, the subject is eligible for this study. In the event the HCV RNA test cannot be performed, the subject is not eligible for this study.
• Tests positive for HBV surface antigen (HBsAg), regardless of the results of other hepatitis B tests. Subjects who test positive only for core antibody (anti-HBc) must undergo further testing for hepatitis B DNA (HBV DNA test). If the HBV DNA test is positive, the subject is not eligible for this study. If the HBV DNA test is negative, the subject is eligible for this study. In the event the HBV DNA test cannot be performed, the subject is not eligible for this study.
• Is infected with human immunodeficiency virus (HIV; positive serology for HIV antibody).
• Has a concomitant diagnosis or any history of congestive heart failure or demyelinating disease.
• Has current signs or symptoms, or a history of severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic, systemic lupus erythematosus, or psychiatric diseases.
• Has a transplanted organ (except for corneal transplant performed > 3 months prior to screening).
• Has a history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (e.g., nodes in the posterior triangle of the neck, supraclavicular, epitrochlear, or paraaortic areas), or splenomegaly.
• Has any known malignancy or has a history of malignancy (except for basal cell carcinoma; squamous cell carcinoma in situ of the skin; or cervical carcinoma in situ that has been treated with no evidence of recurrence; or squamous cell carcinoma of the skin that has been treated with no evidence of recurrence within 5 years prior to screening).
• Has previously undergone allergy immunotherapy for prevention of anaphylactic reactions.
• Is unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access to veins.
• Has known allergies, hypersensitivity, or intolerance to ustekinumab or adalimumab or their excipients (refer to the ustekinumab Investigator Brochure [IB] and the adalimumab local Prescribing Information).
• Has a clinically significant substance abuse problem (e.g., drugs or alcohol) at screening or during the previous 12 months prior to baseline.
• Is currently or intending to participate in any other study using an investigational agent or procedure during the first 56 weeks in this study.
• Has any condition that, in the opinion of the investigator, would make participation not be in the best interest (e.g., may compromise the well-being) of the subject or that could prevent, limit, or confound the protocol-specified assessments.
  • NOTE: Investigators should ensure that all study enrollment criteria have been met during screening, and in particular, prior to initiating randomization. If a subject’s clinical status changes (including any available laboratory results or receipt of additional medical records) during screening such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the study, before initiating randomization (and first study agent administration). Section 17.4, Source Documentation, describes the required documentation to support meeting the enrollment criteria.