|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Medical condition in easily understood language
|Crohn`s Disease is a gastrointestinal disease
|Diseases [C] - Digestive System Diseases [C06]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10017947 - Gastrointestinal disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The main objectives of this trial are to investigate a first signal of efficacy, safety and tolerability of BI 706321 in combination with ustekinumab treatment compared to placebo with ustekinumab treatment in patients with moderately to severely active CD at 12 weeks.
The primary objective is to estimate the difference in change from baseline in Simple Endoscopic Score for Crohn’s disease (SES-CD) after 12 weeks. The primary treatment comparison will be between treatment groups while on treatment during the 12 week induction period.
|Secondary objectives of the trial
|Trial contains a sub-study
|Principal inclusion criteria
|1. Male or female patients.
2. ≥ 18 – ≤ 75 years, at date of signing informed consent.
3. Diagnosis of 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.
4. Elevated CRP (≥ 5 mg/L) OR elevated fecal calprotectin (≥ 250 μg/g)
5. Symptomatic CD defined as ≥ CDAI 150
6. Presence of mucosal ulcers in at least one segment of the ileum or colon and a SESCD score ≥ 7 (for patients with isolated ileitis ≥4), as assessed by ileo-colonoscopy and confirmed by central independent reviewer(s) before start of study treatment.
7. Patients who are experienced to 1 or 2 TNF antagonists (i.e. biosimilars of a drug are counted as the originator drug, e.g. the switch from infliximab originator to CT-P13 will count as one TNF antagonist exposure) at a dose approved for CD. Patients may have stopped TNF antagonists treatment due to primary or secondary nonresponsiveness, intolerance (see definitions in Appendix 10.7), or for other reasons.
8. May be receiving a therapeutic dose of the following:
o Oral 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
o 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. [Allowed steroid treatments: Locally administered steroids as e.g. intra-articular, nasal inhalation or intra-ocular
administration are allowed.] and/or
o AZA, MP, or MTX, provided that dose has been stable for the 8 weeks immediately prior to randomisation and must continue on this dose until week 12.
9. Women of childbearing potential (WOCBP)1 must be ready and able to use highly effective methods of birth control per International Councila on Harmonisation (ICH) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information or in Section 22.214.171.124.
10. Signed and dated written informed consent in accordance with ICH- Good Clinical Practice (GCP) and local legislation prior to admission to the trial.
|Principal exclusion criteria
|1. Have any current or prior abscesses, unless they have been drained and treated at least 6 weeks prior to rand 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
2.Have comp. of CD such as strictures, stenosis, short bowel syndrome, or any other manifestation that might require surgery, or could preclude the use of SESCD/ CDAI to assess response to therapy, or would possibly confound the evaluation of benefit from treatment with BI 706321
3.Patient with an inflammatory bowel disease (IBD) diagnosis other than CD
4. Have had any kind of bowel resection or diversion within 4 months or any other intraabdominal surgery within 3 months prior to visit 1. Patients with current ileostomy, colostomy, or ileorectal anastomosis are excluded
5.Treatment with any non-biologic medication for IBD (tacrolimus or mycophenolate mofetil, systemic corticosteroids), other than those allowed per inclusion criteria, within 30 days prior to rand any biologic treatment with a TNF-alpha antagonist (adalimumab, infliximab, golimumab, certolizumab pegol) or vedolizumab within 4 weeks prior to rando. (If drug level testing for previously used biologic treatment confirms no detectable drug level before rand, patient can be enrolled despite not having completed 4 week from last treatment) any previous treatment with ustekinumab any previous treatment with an investigational non-biologic or biologic drug for CD 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 rand any prior exposure to rituximab within 1 year prior to randomisation
6. Positive stool examination for C difficile (toxin A/B and GDH ag – test positive) or other intestinal pathogens <30 days prior to randomisation
Re screening can be undertaken following documented successful treat, no sooner than 1 week after last intake of antimicrobial therapy. If stool examination for C. Diff is indeterminate (toxin A/B pos and GDH antigen negative or toxin A/B negative and GDH antigen pos), a reflex PCR test must be done to assess eligibility. A positive PCR test will lead to excl
7. Evidence of colonic moderate/severe mucosal dysplasia or colonic adenomas, unless properly removed
8. Fecal transplant ≤ 30 days prior to rand
9. Increased risk of infectious complics (e.g. recent pyogenic inf, any congenital or acquired immunodeficiency (e.g. Human immunodeficiency virus), 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 w prior to randomiz
10. Live or attenuated vaccination within 4 weeks prior to rand
11. Have received BCG vaccines ≤ 1 year prior to randomisation
12. Active or latent TB:
- Patients with active tuberculosis are excluded.
- Patients will be screened with Interferon Gamma Release Assay (IGRA) such as QuantiFERON or T spot, the patient may also be evaluated for the presence of TB with any additional test required by
local practice. Patients with positive test results are excluded unless patient is known to have had a previous diagnosis of active or latent TB and has completed appropriate treatment per local practice/guidelines within the last 3 years and at least 6 months before first administration
of trial medication under this protocol (patients may be rescreened once
to meet this specific criterion)
- Patients with indeterminate QuantiFERON or invalid/borderline T spot may be re-tested with IGRA (once), and if again inconclusive, should have a Purified Protein Derivative (PPD) skin test.
- If IGRA is not available or result remains indeterminate after repeat
testing, tuberculin skin test (TST) should be performed: A tuberculin skin
test positive reaction ≥10mm (≥5mm if receiving ≥15mg/d prednisone
or its equivalent) is considered positive. Patients with a positive TST are
excluded unless they have completed treatment as above.
13.Presence of clinically significant acute or chronic infections not
otherwise listed, including viral hepatitis, COVID-19, or others based on
investigator's judgement. A patient can be rescreened (up to two times)
if the patient was treated and is cured from the acute infection. If at
screening, PCR test for SARS-CoV-2 is positive and patient is
asymptomatic, re-test SARS-COV-2 PCR test is allowed (up to 4 times) to
confirm patient's eligibility before ileo-colonoscopy and/or visit 2. If re
test SARS-COV-2 PCR test is negative, patient must meet all other
eligibility criteria according to the CTP before patient is randomized at
visit 2. Already performed screening assessment do not need to be
|E.5 End points
|Primary end point(s)
|Absolute change from baseline in Simple Endoscopic Score for Crohn’s disease (SES-CD) at week 12.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
- Percent change in SES-CD from baseline at Week 12
- Endoscopic response (defined as ≥50% 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% 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 mg/L and faecal calprotectin (FCP) < 250 ug/g at week 12
- Biological remission, defined as CRP < 5 mg/L and FCP <250 ug/g at week 48
- Clinical remission at week 12, defined as a Crohn’s Disease Activity Index (CDAI) score of <150
- Clinical remission at week 48, defined as a CDAI score of<150
- Clinical response at week 12, defined by a CDAI reduction from baseline of at least 100 points, or a CDAI score of <150
- Number of patients with treatment-emergent adverse event(TEAE) through end of treatment (EoT) and the residual
effect period (REP) (i.e. through Visit 9)
|Timepoint(s) of evaluation of this end point
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|last visit of the last patient in the whole trial (“Last Patient Completed”).
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months