An Open-Label Extension and Long-term Efficacy and Safety Monitoring Study of Patients with Crohn's Disease Previously Included in the Loss of RESponse to Ustekinumab Treated by Dose Escalation Study

The study is a prospective, open-label study only enrolling patients that were previously included in the REScUE study (n=max. 108; NCT04245215) and that terminated that study at week 48. Patients will undergo most necessary examinations, including endoscopy, as part of the Week 48 visit of the REScUE study and those should therefore not be repeated as part of Week 0 visit of the REScUE-OLE study (W0 REScUE-OLE = W48 REScUE). The FACIT-Fatigue scale and the additional laboratory evaluations (serum creatinine, ALT, AST and conjugated bilirubin) are the only examinations that are not foreseen at the end of the REScUE study at week 48. During the 4-week period following the start of REScUE-OLE (= end of REScuE at Week 48), collection and monitoring of the patient's data within the REScUE study will first be finalized, after which unblinding takes place. Depending on the final outcome and treatment of the patient in REScUE ("Q8w responders", "Q8w non-responders", "Q4w responders"), the OLE treatment regimen will be decided as follows:

1. Patients previously enrolled to the ustekinumab 90 mg SC Q8w-arm will continue ustekinumab 90 mg SC Q8w if they are "Q8w responders" at the end of REScUE, defined by the following criteria:

   • Concomitant steroid use <= 20 mg prednisone equivalents (budesonide <=6 mg; beclomethasone dipropionaat <= 5 mg) for at least 28 days before the end of REScUE at week 48 AND

   • Clinical remission (defined as average AP <=1 and average SF <=3) OR clinical response (defined as a drop of at least 50% in average AP and/or a drop of at least 50% in average SF as compared to REScUE baseline, and both average AP and SF no worse than REScUE baseline) AND

   • Endoscopic remission (defined as a total SES-CD <5) OR endoscopic response (defined as a drop of at least 50% in total SES-CD score as compared to REScUE baseline)

2. Patients previously enrolled to the ustekinumab 90 mg SC Q8w-arm will switch to ustekinumab 90 mg SC Q4w ("Cross-over") if they are "Q8w non-responders" at the end of REScUE, defined as failing to meet the criteria for continuation of ustekinumab 90 mg SC Q8w as described above (in 1).

3. Patients previously enrolled to the ustekinumab 90 mg SC Q4w-arm will continue ustekinumab 90 mg SC Q4w if they are "Q4w responders" at the end of REScUE, defined by the following criteria:

   • Concomitant steroid use <=20 mg prednisone equivalents (budesonide <=6 mg; beclomethasone dipropionaat <=5 mg) for at least 28 days before the end of REScUE at week 48 AND

   • Clinical remission (defined as average AP <=1 and average SF <=3) OR clinical response (defined as a drop of at least 50% in average AP and/or a drop of at least 50% in average SF as compared to REScUE baseline, and both average AP and SF no worse than REScUE baseline) AND

   • Endoscopic remission (defined as a total SES-CD <5) OR endoscopic response (defined as a drop of at least 50% in total SES-CD score as compared to REScUE baseline)

4. Patients previously enrolled to the ustekinumab 90 mg SC Q4w-arm will be excluded from continuation of treatment within REScUE-OLE ("Screen failure") if they are "Q4w non-responders" at the end of REScUE, defined as failing to meet the criteria for continuation of ustekinumab 90 mg SC Q4w as described above (in 3).

The consecutive CD treatment after REScUE-OLE cessation is at the discretion of the treating physician.

During the REScUE-OLE study, patients will have on-site, scheduled visits at 5 different timepoints. At each of these visits, the following study procedures will take place: registration of current (CD and non-CD) treatment, assessments of (serious) adverse events, disease activity assessment (PRO-2), physical examination, weight assessment, assessment of vital signs (blood pressure and pulse), laboratory evaluation (including CRP, haemoglobin, thrombocytes, serum albumin, serum creatinine, ALT, AST, conjugated bilirubin, and FC), patient diary review and instruction, and administration of commercially available ustekinumab 90 mg SC. At week 56 and at the end of the study at week 112, these study procedures will be complemented with pharmacokinetic sampling, an ileocolonoscopy and a monitoring of quality-of-life, work and productivity impairment and fatigue, using dedicated questionnaires. For all visits, a window of maximum 7 days is authorized. In between on-site visits, the administration of the medication is allowed off-site, following the schedule of the OLE treatment arm in which they are allocated. This can either be done by self-administration, for patients who have been trained to self-administer, or by a qualified medical professional.

Steroid use at the start and during the study is possible, but a strict tapering regimen is mandatory. Dose-escalation or (re-)initiation of steroids is allowed for a maximum of two times during the study period, with at least 6 months between the first and the second steroid dose-escalation/(re-)initiation. Patients treated with ustekinumab 90 mg SC Q8w will be able to cross-over to a ustekinumab 90 mg SC Q4w regimen if they meet the criteria of CD worsening at week 12 or at any timepoint beyond week 12 after entering REScUE-OLE. Patients treated with a OLE treatment regimen of ustekinumab 90 mg SC Q4w will stop the REScUE-OLE study and discontinue ustekinumab within the REScUE-OLE study, if they meet the criteria of CD worsening at two different timepoints (separated by at least 4 weeks) beyond week 12 after initiation of this OLE treatment regimen.

Primary endpoint of the REScUE-OLE study (sustained steroid-free clinical remission) will be assessed at week 112.