Loss of RESponse to Ustekinumab Treated by Dose Escalation

Loss of RESponse to Ustekinumab Treated by Dose Escalation

The aim of the study is to investigate the effect of re-induction with ustekinumab ≈6mg/kg IV followed by two different maintenance dosing regimens 90 mg subcutaneous every 8 weeks (Q8W) vs 90 mg subcutaneous every 4 weeks(Q4W) on clinical, biological and pharmacological outcomes in patients with Crohn's disease who show a secondary loss of response over time

The study is a prospective double blind interventional study in patients with Crohn Disease treated with ustekinumab that show an objective secondary loss of response to ustekinumab after induction treatment (>Week 16). Patients can be screened during a four week period. The screening includes a clinical, biochemical and endoscopic assessment. Patients will be randomized 8 weeks after the last subcutaneous injection with ustekinumab. All patient will receive an intravenous re-induction with ustekinumab ≈6mg/kg at baseline (8 weeks after last subcutaneous administration). After the intravenous re-induction, the patients receive either ustekinumab 90 mg subcutaneous Q4W or Q8W (altered with q8w placebo to mimic Q4W injections) till week 48. Clinical and biochemical evaluation will be planned every 8 weeks until week 36 with a final evaluation at week48. Primary endpoint will be assessed at week 48. Final assessment at week 48 will include clinical, biochemical and endoscopic evaluation.

Inclusion Criteria:

1. ≥18 years
2. Diagnosis of Crohn's disease by endoscopic and/or radiologic examination.
3. Patient currently treated with ustekinumab, independent of previous biological exposure.
4. Patients treated with maintenance dose of ustekinumab subcutaneous 90 mg every 8 weeks
5. Documented primary response at any time point during induction (up to week 20) defined as a clinical response (physician discretion) AND confirmed by either any of the following:

1. A documented decrease in biomarkers based on a value during induction period compared to a value prior to ustekinumab induction (max. 3 months prior to start of ustekinumab induction)

a. A decrease in CRP OR b. A decrease in FCP 2. A documented endoscopic improvement (evaluation during the induction period compared to an evaluation prior to ustekinumab induction (max. 6 months prior to start of ustekinumab induction) 6. Documented loss of response after induction (at any timepoint after week 16) assessed by the physician as moderate to severe active Crohn's disease. The increase in symptoms reported by the patient is defined as Patient Reported Outcome-2 (Abdominal Pain > 1 AND Stool Frequency > 3) AND confirmed by either any of the following* :

1. Documentation of endoscopic lesions in at least one segment of the ileum or colon as assessed by ileocolonoscopy AND a documented increase in biomarkers based on an increased value compared to the lowest value obtained during induction or after week 16 ustekinumab induction

   1. An increase in CRP and > 5 mg/L OR
   2. An increase in FCP and > 250µg/mg

2. A documented relapse on endoscopy : Presence of mucosal ulcers in at least one segment of the ileum or colon and a SES-CD ≥ 6 (for patients with isolated ileitis ≥ 4), as assessed by ileocolonoscopy.

7. Adequate contraception in female of reproductive age (oral contraception, intra uterine device, sterilisation or barrier method) 8. Have the capacity to understand and sign an informed consent form. 9. Be able to adhere to the study visit schedule and other protocol requirements.

10. All Crohn's Disease treatments stable for at least 2 weeks prior to baseline.

* the criterium used to proof loss of response does not have to be identical to the one used to proof primary response : e.g. one can use an increase in biomarkers to proof primary response and a relapse on endoscopy to proof loss of response

Exclusion Criteria:

1. Ongoing treatment with

   1. other concomitant biological (vedolizumab, anti-TNF)
   2. Steroids >20 mg prednisolone or equivalent at baseline (budesonide >6 mg, > 5mg beclomethasone dipropionate at baseline)
   3. Q4w ustekinumab (ustekinumab treatment every four weeks)

2. Women that are pregnant, nursing, or planning pregnancy

3. Have screening laboratory test results within the following parameters:

   1. Haemoglobin < 8.5 g/dL
   2. Platelets < 100,000 /mm3
   3. Serum creatinine ≥ 1.7 mg/dL
   4. aspartate aminotransferase and alanine aminotransferase > 3 times the upper limit of normal range
   5. Direct (conjugated) bilirubin ≥ 3.0 mg/dL.

4. Have current signs or symptoms of infection confirmed by positive stool or blood testing (including gastrointestinal pathogens, tuberculosis, human immunodeficiency virus, hepatitis B, hepatitis C).

5. Patients with a positive stool sample for gastrointestinal pathogen including Clostridium difficile.

6. Evidence of current or previous clinically significant disease, medical condition other than Crohn's Disease, finding of the medical examination, or laboratory value at the screening visit outside the reference range that is of clinical relevance, that in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data.

7. Patients with an ileostomy

8. Patients that received an intravenous re-induction with ustekinumab within the 6 months prior to baseline.

9. Patients with an impassable stenosis even after attempt of endoscopic balloon dilation.

10. Patients with an abscess