A Study to Test Whether BI 706321 Combined With Ustekinumab Helps People With Crohn's Disease

Study Overview
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Brief Summary
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This study is open to adults, aged 18-75 years, with moderate to severe Crohn's disease. The purpose of this study is to find out whether BI 706321 combined with ustekinumab helps people with Crohn's disease. BI 706321 is a medicine being developed to treat Crohn's disease. Ustekinumab is a medicine already used to treat Crohn's disease. Participants are put into 2 groups randomly, which means by chance. One group gets BI 706321 and ustekinumab. The other group gets placebo and ustekinumab. Participants take BI 706321 or placebo as tablets every day. Placebo tablets look like BI 706321 tablets but do not contain any medicine. Ustekinumab is given as an infusion into a vein once at the beginning of the study. After that, ustekinumab is given as an injection under the skin every 2 months. Participants take BI 706321 or placebo in combination with ustekinumab for 3 months. After that, participants receive only ustekinumab for another 9 months. Participants are in the study for about 1 year. During this time, they visit the study site about 13 times. At 3 of the visits, doctors do a colonoscopy to examine the bowel. The results from the colonoscopies are compared between the 2 groups. The doctors also regularly check participants' health and take note of any unwanted effects.

Official Title
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A Phase IIa, Randomised, Double-blind, Placebo-controlled Trial to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of BI 706321 Orally Administered for 12 Weeks in Patients With Crohn's Disease (CD) Receiving Ustekinumab Induction Treatment

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: BI 706321
* Drug: ustekinumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Crohn Disease (CD) for at least 3 months prior to visit 1, as confirmed at any time in the past by endoscopy and/OR, radiology, and supported by histology. Elevated C-reactive protein (≥ 5 mg/L) OR elevated fecal calprotectin (≥ 250 µg/g) Symptomatic CD defined as Crohn's Disease Activity Index (CDAI) ≥150. Presence of mucosal ulcers in at least one segment of the ileum or colon and a Simple Endoscopic Score for Crohn's disease (SES-CD) score ≥ 7 (for patients with isolated ileitis ≥4). Patients who are experienced at least 1 tumor necrosis factor (TNF) antagonists at a dose approved for CD. Patients may have stopped TNF antagonist treatment due to primary or secondary non-responsiveness, intolerance, or for other reasons. May be receiving a therapeutic dose of the following: Oral 5-aminosalicylic acid (5-ASA) compounds must have been at a stable dose for at least 4 weeks prior to randomisation and must continue on this dose until week 12 and/or Oral corticosteroids if indicated for treatment of CD must be at a prednisone equivalent dose of ≤ 20 mg/day, or ≤ 9 mg/day of budesonide, and have been at a stable dose for at least 2 weeks immediately prior to randomisation and must continue on this dose until week 12. and/or Azathioprine (AZA), mercaptopurine (MP), or methotrexate (MTX), provided that dose has been stable for the 8 weeks immediately prior to randomisation and must continue on this dose until week 12. Women of childbearing potential must be ready and able to use highly effective methods of birth control. Further inclusion criteria apply Exclusion Criteria: Have any current or prior abscesses, unless they have been drained and treated at least 6 weeks prior to randomisation and are not anticipated to require surgery. Patients with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses present based on investigator's judgement. Have complications of CD such as strictures, stenosis, short bowel syndrome, or any other manifestation that might require surgery, or could preclude the use of SES-CD/CDAI to assess response to therapy, or would possibly confound the evaluation of benefit from treatment with BI 706321 (based on investigator's judgement). Patient with an inflammatory bowel disease (IBD) diagnosis other than CD. Have had any kind of bowel resection or diversion within 4 months or any other intra-abdominal surgery within 3 months prior to visit 1. Patients with current ileostomy, colostomy, or ileorectal anastomosis are excluded. Treatment with: Any non-biologic medication for IBD (e.g.tacrolimus or mycophenolate mofetil, systemic corticosteroids), other than those allowed per inclusion criteria, within 30 days prior to randomisation Any biologic treatment with a TNF-alpha antagonist (adalimumab, infliximab, golimumab, certolizumab pegol) or vedolizumab (or a biosimilar of these drugs) within 4 weeks prior to randomisation. (If drug level testing for previously used biologic treatment confirms no detectable drug level before randomisation, patient can be enrolled despite not having completed 4 week from last treatment.) Any previous treatment with ustekinumab (or a biosimilar of this drug) Any previous treatment with an investigational (or subsequently approved) non-biologic/biologic drug for CD (including but not limited to JAK inhibitors [e.g. upadacitinib], S1P modulators, IL-23 inhibitors [e.g. risankizumab], antiintegrins). Any investigational drug for an indication other than CD during the course of the actual study and within 30 days or 5 half-lives (whichever is longer) prior to randomisation. Any prior exposure to rituximab within 1 year prior to randomisation. Positive stool examination for C difficile or other intestinal pathogens <30 days prior to randomization Evidence of colonic moderate/severe mucosal dysplasia or colonic adenomas, unless properly removed Increased risk of infectious complications (e.g. recent pyogenic infection, any congenital or acquired immunodeficiency (e.g. human immunodeficiency virus (HIV)), past organ or stem cell transplantation (with exception of a corneal transplant > 12 weeks prior to screening) or have ever received stem cell therapy (e.g., Prochymal). Prior treatment with a somatic cell therapy product (e.g., Alofisel) is not excluded, provided it was administered > 8 weeks prior to randomisation. Live or attenuated vaccination within 4 weeks prior to randomisation. Presence of clinically significant acute or chronic infections not otherwise listed, including viral hepatitis, COVID-19, or others based on investigator's judgement. A marked baseline prolongation of QT/QTc interval (such as QTcF intervals that are greater than 450 ms for men, 470 ms for female) or any other relevant electrocardiogram (ECG) finding at screening. Both have to be confirmed by repeated ECG recording. Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Ustekinumab treatment is open-label for the Sponsor, patients and investigator/site staff.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 706321 + ustekinumab<br> | Drug: BI 706321<br>* BI 706321<br>Drug: ustekinumab<br>* ustekinumab<br>|
| Placebo Comparator: Placebo + ustekinumab<br> | Drug: ustekinumab<br>* ustekinumab<br>Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change from baseline in Simple Endoscopic Score for Crohn's disease (SES-CD) at week 12 | SES-CD assesses the size of mucosal ulcers, the ulcerated surface, the endoscopic extension and the presence of stenosis. Each variable is scored from 0 to 3 for different parts of the intestine. A total score from 0 to 2 represents remission, 3 to 6 represents mild endoscopic activity, 7 to 15 represents moderate endoscopic activity and > 15 represents severe endoscopic activity. | At week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in Simple Endoscopic Score for Crohn's disease (SES-CD) from baseline at Week 12 | SES-CD assesses the size of mucosal ulcers, the ulcerated surface, the endoscopic extension and the presence of stenosis. Each variable is scored from 0 to 3 for different parts of the intestine. A total score from 0 to 2 represents remission, 3 to 6 represents mild endoscopic activity, 7 to 15 represents moderate endoscopic activity and > 15 represents severe endoscopic activity. | At week 12 | 
| Endoscopic response | defined as > 50 percent (%) SES-CD reduction from baseline or for a induction baseline SES-CD of 4, at least a 2 point reduction from induction baseline | At week 12 | 
| Endoscopic response | defined as > 50 percent (%) SES-CD reduction from baseline or for a induction baseline SES-CD of 4, at least a 2 point reduction from induction baseline | At week 48 | 
| Endoscopic remission | defined as SES-CD score of ≤ 2 | At week 12 | 
| Endoscopic remission | defined as SES-CD score of ≤ 2 | At week 48 | 
| Biological remission | defined as C-Reactive Protein (CRP) < 5 milligrams/Litre (mg/L) and faecal calprotectin (FCP) < 250 micrograms/gram (ug/g) | At week 12 | 
| Biological remission | defined as C-Reactive Protein (CRP) < 5 milligrams/Litre (mg/L) and faecal calprotectin (FCP) < 250 micrograms/gram (ug/g) | At week 48 | 
| Clinical remission | defined as a Crohn's Disease Activity Index (CDAI) score of < 150 CDAI is comprised of eight variables which are summed after adjustment with a weighting factor. A CDAI score of ≤ 150 represents remission, 151 to 219 represents mild activity, 220 to 450 represents moderate activity and a score of > 450 represents severe or very severe activity. | At week 12 | 
| Clinical remission | defined as a Crohn's Disease Activity Index (CDAI) score of < 150 | At week 48 | 
| Clinical response | defined by a CDAI reduction from baseline of at least 100 points, or a CDAI score of < 150 | At week 12 | 
| Number of patients with treatment-emergent adverse event (TEAE) through end of treatment (EoT) and the REP period |  | Up to 104 days |