Crohn's Disease: Pharmacokinetics, Efficacy, and Safety of Risankizumab in Pediatric Subjects with Moderately to Severely Active Crohn's Disease

Prior treatment

• Female subjects may not be pregnant, breastfeeding, or considering becoming pregnant during the study or for approximately 147 days (21 weeks or as guided by the local risankizumab label [if approved], whichever is longer) after the last dose of study drug.
• Subject must not have received any replicating live viral or bacterial vaccine within 4 weeks prior to the first dose of study drug or expect the need for live vaccination during study participation including at least 140 days (20 weeks or as guided by the local risankizumab label [if approved], whichever is longer) after the last dose of study drug.
• Subjects are excluded if: (a) Subject on CD-related antibiotics who has not been on stable doses for greater than, or discontinued within, 14 days prior to Baseline. (b) Subject on oral aminosalicylates who has not been on stable doses for greater than, or discontinued within, at least 14 days prior to Baseline. (c) Subject taking oral corticosteroids: • Budesonide > 9 mg/day • Prednisone or equivalent > 20 mg/day, or • Has not been on the current course for ≥ 14 days prior to Baseline and on a stable dose for ≥ 7 days prior to Baseline. (d) Subject on IMMs (AZA, 6-MP, MTX) who: • Has not been on the current course for ≥ 42 days prior to Baseline • Has not been on a stable dose for ≥ 28 days prior to Baseline, or • Has stopped IMM ≤ 28 days prior to Baseline
• For medications and treatments taken during the Screening Period, subjects are excluded if: (a) Subjects on growth hormone who have not been on a stable dose for at least 12 weeks prior to Baseline. Subjects must consent to remain on a stable dose through the duration of the study. (b) Subject who received IV anti-infectives within 28 days prior to Baseline visit or oral/intramuscular anti-infectives (non-CD-related) within 14 days prior to the Baseline visit. This does not apply to TB prophylaxis. (c) Subject who received total parenteral nutrition within 28 days prior to Baseline. (d) If receiving exclusive enteral nutrition, must have been on a stable regimen for at least 2 weeks prior to Baseline. (e) Subject who received oral cyclosporine, oral tacrolimus, mycophenolate mofetil, or thalidomide within 28 days prior to Baseline. (f) Subject who received fecal microbial transplantation within 28 days prior to Baseline.
• The following prior medications and treatments are not allowed: (a) Subject who received any: • Biologic agent: infliximab and/or adalimumab, including biosimilars, within 2 half-lives (3 and 4 weeks, respectively) prior to Baseline. Or • Any investigational biologic or other agent or procedure within 30 days or 5 half-lives prior to Baseline, whichever is longer, or currently enrolled in another interventional clinical study. (b) Subject with prior exposure to p19 inhibitors (e.g., risankizumab and mirikizumab). (c) Subject has been taking combination of oral budesonide and oral prednisone (or equivalent), with the exception of inhalers, within 14 days prior to Screening or during the Screening period. (d) Subject who received IV/intramuscular corticosteroids during the Screening period. (e) Subject who received therapeutic enema or suppository, other than required for endoscopy during the Screening period. (f) Subject who received apheresis (e.g., Adacolumn apheresis) ≤ 60 days prior to Screening or during the Screening period. (g) Subject who has concomitant cannabis use either recreational or for medical reasons within 14 days of Baseline or any history of clinically significant drug or alcohol abuse in the last 6 months.
• Subject must not have had a major surgery performed within 12 weeks prior to Baseline or planned during the conduct of the study (e.g., inguinal hernia repair, cholecystectomy, intestinal resection).
• Subject must not have any of the following medical disorders: (a) Current diagnosis of ulcerative colitis, indeterminate colitis, or monogenic IBD. (b) A diagnosis of CD prior to 2 years of age. (c) A diagnosis or suspected diagnosis of a primary immunodeficiency. (d) Currently known complications of CD such as: • Active abscess (abdominal or perianal); • Symptomatic bowel strictures; • 2 missing segments of the following 5 segments: terminal ileum, right colon, transverse colon, sigmoid and left colon, and rectum; • Fulminant colitis; • Toxic megacolon; • Or any other manifestation that might require surgery while enrolled in the study. (e) Ostomy or ileoanal pouch. (f) Diagnosis of short gut or short bowel syndrome. (g) Surgical bowel resection within the past 3 months prior to Baseline (excluding gastrointestinal surgeries which are not bowel resections such as appendectomy or ostomy closure), or a history of >3 bowel resections.
• Subjects must not have evidence of: (a) HBV or HCV infection, defined as: • HBV: HBs Ag positive (+) test or detected sensitivity on the HBV DNA PCR qualitative test for subjects who are HBc Ab positive (+) (and for HBs Ab positive [+] subjects where mandated by local requirements). • HCV: HCV RNA detectable in any subject with anti-HCV Ab. (b) HIV, defined as confirmed positive anti-HIV Ab test. Note: In case a screened subject has a confirmed positive HIV Ab test, eligibility criterion 11 (Subject is judged to be in good general health criteria…) should be selected in eCRF for documentation of screening failure. (c) Active TB. For subjects with latent TB, please see Section 3.13 of the Operations Manual (Appendix J). (d) Active systemic infection/clinically important infection during the last 2 weeks prior to Baseline visit as assessed by the investigator. (e) Any infection with C. difficile or other intestinal pathogen during Screening.
• Subjects must not have any of the following medical diseases or disorders: (a) Recent (within past 6 months) cerebrovascular accident or MI. (b) History of an organ transplant which requires continued immunosuppression. (c) Active or suspected malignancy or history of any malignancy within the last 5 years except for successfully treated NMSC or localized carcinoma in situ of the cervix. (d) Previous history of dysplasia of the gastrointestinal tract or found to have dysplasia, other than completely removed low-grade dysplastic lesions, in any biopsy performed during the Screening endoscopy.
• Subject must not have concurrent clinically significant medical conditions other than the indication being studied or any other reason that the investigator determines would interfere with the subject's participation in this study, would make the subject an unsuitable candidate to receive study drug, or would put the subject at risk by participating in the study.

Other illness

• Subject must not have a history of clinically significant (per investigator's judgement) drug or alcohol abuse within the last 6 months.
• Subject must not have a history of hereditary fructose intolerance (a rare genetic condition) or an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same class.
• In subjects who tested positive for COVID-19, at least 5 days have passed since a COVID-19 positive test result in asymptomatic subjects. Subjects with mild/moderate COVID-19 infection can be enrolled if resolution of fever without use of antipyretics for 24 hours and improvement in other symptoms or 5 days since the COVID-19 positive test result (whichever comes last). Subject may be re-screened if judged to be in good general health, as determined by the investigator based upon the medical history and physical examination.

Other

• Employees of the sponsor and/or study sites and their immediate family members may not be enrolled in this study.

• Subjects and/or their legally authorized representative must voluntarily sign and date an informed consent (and assent for minors as required by applicable regulation), approved by an IEC/IRB, prior to the initiation of any screening or study-specific procedures. In Japan, a subject's parent or legal guardian must be willing to give written informed consent. In China, the legal guardian must be willing to give written informed consent; subjects aged 8 to < 18 years must also be willing to give written informed consent.
• Weight at the time of Screening and Baseline must be ≥ 10 kg.
• Laboratory values meeting the following criteria within the Screening period prior to the first dose of study drug: • Serum ALT ≤ 2 × ULN; • Serum AST ≤ 2 × ULN; • Serum total bilirubin < 2 mg/dL; except for subjects with isolated elevation of indirect bilirubin relating to Gilbert syndrome; • Total WBC count ≥ 3,000/μL; • ANC ≥ 1,500/µL; • Platelet count ≥ 100,000/µL; • Hemoglobin ≥ 8 g/dL (80 g/L).
• Confirmed diagnosis of CD at least 3 months (90 days) prior to Baseline. Appropriate documentation of biopsy results consistent with the diagnosis of CD, in the assessment of the investigator, must be available.
• Must have moderately to severely active CD, as defined by the PCDAI score > 30 assessed at Baseline.
• Must have endoscopic evidence of mucosal inflammation as documented by the SES-CD of ≥ 6 for ileocolonic or colonic disease (or SES-CD of ≥ 4 for isolated ileal disease). All eligible scores exclude the presence of narrowing component and are confirmed by a central reader.
• Demonstrated intolerance or IR to one or more of the following categories of drugs: aminosalicylates (this drug class is not sufficient for eligibiliy for subjects in FR, IT, NL, ES and SE), oral locally acting corticosteroids, systemic steroids (prednisone or equivalent), IMMs, and/or biologic therapies.
• Subject is judged to be in good general health, as determined by the investigator based upon the results of a medical history, physical examination, laboratory profile, and a 12-lead ECG performed during the Screening period.
• Subjects with CD involving the colon of > 9 years' duration must have documented evidence of a negative surveillance colonoscopy for dysplasia within 24 months before Baseline.
• Females of child-bearing potential must have a negative serum pregnancy test at the Screening visit and a negative urine pregnancy test at Baseline prior to the first dose of study drug. • Subjects with a borderline serum pregnancy test at Screening must have absence of clinical suspicion of pregnancy or other pathological causes of borderline results and a serum pregnancy test ≥3 days later to document continued lack of a positive result (unless prohibited by local requirements). • Urine pregnancy test: Subjects with a urine pregnancy test at Baseline that is borderline or ambiguous must have a serum pregnancy test. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• Female subjects of childbearing potential must practice at least 1 protocol-specified method of birth control, from Baseline through at least 147 days (21 weeks or as guided by the local risankizumab label [if approved], whichever is longer) after the last dose of study drug (local practices may require 2 methods of birth control; refer to Section 5.2 for more details on change in childbearing potential of female subjects and contraception). Female subjects of nonchildbearing potential do not need to use birth control.
• Are willing and able to comply with procedures required in this protocol.
• Pediatric individuals, 2 to < 18 years old. If a subject turns 18 years old at any point after Baseline, they may continue in the study. • PK Cohort 1 – ages include 6 to < 18 years at the time of Baseline. • PK Cohort 2 – ages include 2 to < 6 years at the time of Baseline. • Expansion Cohort 3 – ages include 2 to < 18 years at the time of Baseline.