Ensayos clínicos

Inclusion Criteria:

• Male or female aged ≥ 18 years (or the legal age of consent in the jurisdiction in which the study is taking place if older than 18 years).
• A history of Crohn’s disease or fistulizing Crohn’s disease of at least 3 months’ duration, with colitis, ileitis, or ileocolitis, confirmed at any time in the past by radiography, histology, and/or endoscopy.
• Initially responded to ustekinumab induction therapy*, administered according to the local label, followed by secondary LoR to ustekinumab**.
• * Initial response to ustekinumab as defined in Section 10.2, Appendix 2.
• **Secondary LoR to ustekinumab is defined as active disease at study baseline, proven by a CDAI score of ≥ 220 and ≤ 450 with at least one of the following:
  • Elevated CRP (>3.0 mg/L); and/or
  • Elevated fCal (> 250 mg/kg); and/or
  • Endoscopy (performed ≤ 3 months before baseline) with evidence of active Crohn’s disease (defined as one or more ulcerations in the ileum and/or colon).
  • Participants must currently be on a SC 90 mg ustekinumab q8w maintenance dose regimen and have received at least 2 doses of SC 90 mg ustekinumab treatment 8 weeks apart prior to enrollment.
• The following medications for the treatment of Crohn’s disease are permitted providing the doses indicated are stable for at least 3 weeks before baseline or have been discontinued at least 3 weeks before baseline:
  • Oral 5-aminosalicylic acid (5-ASA) compounds;
  • Oral corticosteroids (e.g., prednisone, budesonide) at a prednisone-equivalent dose of ≤ 40 mg/day or ≤ 9 mg/day of budesonide;
  • Antibiotics used as the primary treatment of Crohn’s disease. Any participants receiving conventional immunomodulators (i.e., azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) must have been taking them for ≥ 12 weeks and must have been on a stable dose for a least 4 weeks before baseline.
• The following laboratory test results are within the specified limits at screening:
  • Hemoglobin ≥ 8.5 g/dL (≥ 85 g/L);
  • White blood cell (WBC) count ≥ 3.5 x 10^3 /µL (≥ 3.5 GI/L);
  • Neutrophils ≥ 1.5 x 10^3 /µL (≥ 1.5 GI/L);
  • Platelets ≥ 100 x 10^3 /µL (≥ 100 GI/L);
  • Serum creatinine < 1.7 mg/dL (≤ 150 µmol/L);
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase levels ≤ 2 times the upper limit of normal for the laboratory conducting the test;
  • Direct (conjugated) bilirubin < 1.0 mg/dL (<0.01 g/L).
    • NOTE: A repeat of these screening laboratory tests is allowed during the screening phase. The investigator may consider the participant eligible if the previously abnormal laboratory test result is within the acceptable range on repeat testing in the laboratory.
• Meet the following TB screening criteria:
  • No history of latent or active TB before screening. An exception is made for participants who have a history of latent TB and are currently receiving treatment for latent TB, will initiate treatment for latent TB prior to first administration of study intervention, or 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 TB treatment and provide appropriate documentation.
  • No signs or symptoms suggestive of active TB upon medical history and/or physical examination.
  • No recent close contact with a person with active TB. If there has been such contact, the participant will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, will receive appropriate treatment for latent TB prior to or simultaneously with the first administration of study intervention.
  • Within 5 weeks before the first administration of study intervention, has a negative QuantiFERON®-TB test result, 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 prior to the first administration of study intervention. If the QuantiFERON-TB test is not approved or is not registered in a country or if the tuberculin skin test is mandated by local health authorities, a negative tuberculin skin test or a newly identified positive tuberculin skin test 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, is additionally required within 5 weeks prior to the first administration of study intervention.
  • Participants who have an indeterminate result should have the test repeated. Participants with persistently indeterminate QuantiFERON-TB test results may be enrolled without treatment for latent TB if active TB is ruled out, their chest radiograph shows no abnormality suggestive of TB (active or old, inactive TB), and the participant has no additional risk factors for TB as determined by the investigator. This determination must be promptly reported to the sponsor’s medical monitor, recorded in the participant's source documents, and initialed by the investigator.
    • NOTE: The QuantiFERON-TB test and/or the tuberculin skin test is/are not required to be performed at screening for participants with a history of latent TB and ongoing treatment for latent TB or documentation of having completed adequate treatment as described above. Participants with documentation of having completed adequate treatment as described above are not required to initiate additional treatment for latent TB.
  • Has a chest radiograph (at least a posterior-anterior view) or computed tomography of the chest, taken within 6 months before the first administration of study intervention and read by a qualified radiologist, with no evidence of current, active TB or old, inactive TB.
  • A female participant must be:
  • Not of childbearing potential; OR
  • If heterosexually active, must be practicing a highly effective method of birth control, consistent with local regulations regarding the acceptable methods of contraception for those participating in clinical studies, for the duration of their participation in the study and for 15 weeks after the last dose of study intervention, the end of relevant systemic exposure.
    • NOTE: If the participant’s childbearing potential changes after the start of the study, that participant must begin practicing a highly effective method of birth control as described above; OR
    • Not be heterosexually active and agrees to utilize a highly effective method of birth control if they become heterosexually active during their participation in the study.  
  • All female participants of childbearing potential must have a negative highly sensitive serum (β-human chorionic gonadotropin [β-hCG]) pregnancy test at screening and a negative urine pregnancy test at baseline and prior to each administration of study intervention.
• A male participant who is heterosexually active with a woman of childbearing potential and is not surgically sterile must agree to use a double-barrier method of birth control and not donate sperm during the study and for 15 weeks after receiving study intervention.
• Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
• Sign an informed consent document indicating that he/she understands the purpose of and procedures required for the study and is willing to participate in the study

Exclusion Criteria:

• 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 ustekinumab.
• 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 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 there are currently no abscesses identified.
• Any kind of bowel resection within 6 months or any other intra-abdominal surgery within 3 months before baseline.
• A draining (i.e., functioning) stoma or ostomy
• Received any of the following prescribed medications or therapies within the specified period:
  • Use of IV ustekinumab re-induction after the initial weight-tiered-based IV induction dose of ustekinumab;
  • Any known history of shortened frequency of SC dose administration (< q8w) for a secondary loss of response where the participant did not, in the opinion of the treating physician, benefit from the dose interval shortening;
  • Intravenous corticosteroids as a treatment for Crohn’s disease within 3 weeks before 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) within 4 weeks before baseline;
    • NOTE: See Inclusion Criterion above for restrictions on typical immunomodulator agents (AZA, 6-MP or MTX).
  • Any other investigational agent for Crohn’s disease (e.g., other biologics, small molecules or anti-sense RNA such as mongersen), unless at least 3 months or 5 halflives (whichever is longer) have elapsed since the last dose;
  • Treatment with apheresis (e.g., Adacolumn apheresis) or total parenteral nutrition as a treatment for Crohn’s disease within 3 weeks before baseline.
• A stool culture or other examination in the last 4 months that is positive for an enteric pathogen, including Clostridium difficile toxin, unless a repeat examination is negative and there are no signs of ongoing infection with that pathogen.
• Received a Bacille Calmette-Guérin (BCG) vaccination within 12 months before baseline or any other live bacterial or live viral vaccination within 2 weeks before baseline.
• 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 (e.g., recurrent pyelonephritis or chronic nonremitting cystitis), or open, draining, or infected skin wounds or ulcers.
• Any current signs or symptoms of infection. Established non-serious infections (e.g., acute upper respiratory tract infection, simple urinary tract infection) need not be considered exclusionary at the discretion of the investigator.
• A history of serious infection (e.g., sepsis, pneumonia, or pyelonephritis), including any infection requiring hospitalization or IV antibiotics, for 8 weeks before baseline.
• Evidence of a herpes zoster infection ≤ 8 weeks before baseline.
• A history of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, before screening; refer to Inclusion Criterion above for information regarding eligibility with a history of latent TB.
• 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.
• A current or (lifetime) history of a nontuberculous mycobacterial infection or serious opportunistic infection (e.g., Cytomegalovirus colitis, Pneumocystis carinii, aspergillosis).
• Known to be infected with human immunodeficiency virus, hepatitis B, or hepatitis C.
• Severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or any signs or symptoms thereof.
• A transplanted organ, with the exception of a corneal transplant performed > 12 weeks before screening.
• A known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
• Any known malignancy or a history of malignancy, with the exception of: basal cell carcinoma; squamous cell carcinoma in situ of the skin; cervical carcinoma in situ that has been treated with no evidence of recurrence; or squamous cell carcinoma of the skin that was treated with no evidence of recurrence within 5 years before screening.
• Previous allergy immunotherapy for prevention of anaphylactic reactions.
• Unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access to veins.
• Known to have had a substance abuse (drug or alcohol) problem within the 12 months before baseline.
• Known allergies, hypersensitivity, or intolerance to ustekinumab or its excipients (refer to the Investigator's Brochure for further details).
• Currently is participating in or is intending to participate in any other study using an investigational agent or procedure during participation in this study.
• A woman who is pregnant, or breastfeeding, or planning to become pregnant, or is a man who plans to father a child while enrolled in this study or within 15 weeks after the last dose of study intervention.
• Any condition that, in the opinion of the investigator, would make study participation not in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• During the 6 weeks prior to baseline, have had ANY of:
  • confirmed SARS-CoV-2 (COVID-19) infection (test positive); OR
  • suspected SARS-CoV-2 infection (clinical features without documented test results); OR
  • 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 obtained at least 2 weeks after conditions (a), (b), or (c) above (timed from resolution of key clinical features if present; e.g., fever, cough, dyspnea) AND with absence of ALL conditions (a), (b) and (c) above during the period between the negative test result and the baseline study visit. 
  • Exclusion: If a patient is excluded due to recent COVID-19-related features, the reason for screen failure should be documented in the case report form (CRF) under the exclusion criterion of having a condition for which study participation would not be in the patient’s interest or could confound study assessments.
  • The field of COVID-related testing (for presence of, and immunity to, the SARS-CoV-2 virus) is rapidly evolving. Additional testing may be performed as part of screening and/or during the study if deemed necessary by the investigator and in accordance with current regulations, guidance from authorities, or standards of care.