This is a study in adults with Crohn's Disease who also have fistulas near the anus. The study has 2 parts. The first part is to find out more about what causes the fistulas. In this part of the study, tissue samples are taken from patients. The second part of the study tests whether a medicine called spesolimab (BI 655130) helps patients with Crohn's Disease.

Participants get study medication for 24 weeks. The participants are put into 2 groups. It is decided by chance who gets into which group. One group gets an intravenous drip that contains spesolimab every 4 weeks. The other group gets a placebo drip every 4 weeks. The placebo drip looks like the spesolimab drip, but contains no medicine.

The doctors regularly examine fistulas of the participants. The results of the fistula examinations are compared between the groups. The doctors also check the general health of the patients.

Inclusion criteria

• 18-75 years at date of signing informed consent

• Male or female patients. Women of childbearing potential (WOCBP)1 must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. Restrictions regarding women of childbearing potential. Restrictions regarding contraception for female patients are not applicable for Screening Cohort

• Diagnosis of clinical Crohn´s Disease ≥ 3 months prior to screening by clinical and endoscopic evidence and corroborated by a histopathology report

• Has ≥ 1 perianal active* fistula(s) with clinical indication for seton drainage (≥ 4 weeks duration before enrolment, as a complication of CD) **

  * Criteria for Active Fistula: As per clinical evaluation: Presence of spontaneous drainage or drainage after gentle finger compression at the external openings & as confirmed by radiological (MRI) exploration

  ** Patients who are screened with a seton drainage in place are eligible provided the drainage has not been in place for > 3 months and the patient meets the rest of the eligibility criteria

• Absent, mild or moderate clinical activity with CDAI < 250. CDAI is not applicable for Screening Cohort

• Demonstrated in the past inadequate fistula response or loss of response or have had unacceptable side effects with approved doses of at least one of the following compounds: immunosuppressive agents (e.g. thiopurines, methotrexate), TNFɑ antagonists (e.g. infliximab, adalimumab, certolizumab pegol; or respective biosimilars), vedolizumab, ustekinumab, azathioprine and / or antibiotics

• Patients with family history of colorectal cancer or personal history of increased colorectal cancer risk must have had a negative ileocolorectal cancer screening within <1 year prior to screening per local guidance

• Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial

• Further inclusion criteria apply

Gastrointestinal Exclusion Criteria (Study cohort only)

• Complications of Crohn's Disease such as symptomatic strictures, functional stenosis distal from fistula(s), short gut syndrome, or any other manifestation that might require surgery, could preclude the use of the PDAI and CDAI to assess response to therapy, or would possibly confound the evaluation of benefit from treatment with BI 655130

• Rectovaginal fistulas

• Anticipated to require surgical intervention for CD including any fistula surgical procedures (except seton drainage)

• Has an abscess that the investigator feels requires drainage beyond fistula drainage with a seton (based on either clinical assessment or MRI)

• Any kind of bowel resection or diversion within 6 months or any other intraabdominal surgery within 3 months prior to screening.

• Ileostomy, colostomy or known fixed symptomatic stenosis of the intestine at screening

• Positive stool examinations for C. difficile or other intestinal pathogens < 30 days prior to screening

  -- Evidence of colonic mucosal dysplasia or colonic adenomas, unless properly removed (properly according to the investigator's assessment)

• Faecal Microbiota transplant (FMT) within 6 months prior to randomization

• Treatment with:

  • any non-biologic medication (incl. cyclosporine, JAK inhibitors such as tofacitinib, tacrolimus, sirolimus, mycophenolate mofetile, S1P modulators, SMAD7 antisense inhibitors such as mongersen), other than those allowed per chapter 4.2.1 within 30 days prior to randomisation unless these patients show an undetectable plasma concentration
  • any biologic treatment approved for CD other than anti-TNFα inhibitors within 8 weeks prior to randomization unless these patients show an undetectable plasma concentration
  • any investigational or non-approved biologic for CD (including but not limited to IL-23 inhibitors) within 12 weeks prior to randomisation or etrolizumab within 8 weeks prior to randomization unless these patients show an undetectable plasma concentration
  • rectal 5-ASA, rectal Tacrolimus, parenteral or rectal corticosteroids (incl. budesonide) within 2 weeks prior to randomisation
  • any antibiotics within 1 week prior to randomisation
  • any prior autologous or allogeneic, haematopoietic (HSC) or mesenchymal stem cell (MSC) therapy
  • any prior exposure to BI 655130
  • any chronic use of NSAID within 2 weeks prior to randomisation (occasional use of NSAIDs and acetaminophen for headache, arthritis, myalgias, menstrual cramps, etc., and daily use of baby or low dose (81-162.5mg) aspirin for cardiovascular prophylaxis are permitted)
  • any life-attenuated vaccines within 6 weeks prior to randomization

Infectious Disease Exclusion Criteria (Study cohort only)

• Increased risk of infectious complications (e.g. due to past organ or stem cell transplantation)

• Live or attenuated vaccination within 6 weeks prior to randomization

• Patients with a positive QuantiFERON TB test during screening are excluded, unless:

  • Patient had 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 re-screened once to meet this criterion)
  • Patients with suspected false positive or indeterminate QuantiFERON TB result may be re-tested once
  • If Quantiferon not available or providing indeterminate results after repeat testing : A tuberculin skin test reaction ≥10mm (≥5mm if receiving ≥15mg/d prednisone or its equivalent)

• Relevant chronic or acute infections including active tuberculosis, human immunodeficiency virus (HIV) infection or viral hepatitis. A patient can be re-screened if the patient was treated and is cured from the acute infection.

General Exclusion Criteria (Study cohort only)

• Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ carcinoma of uterine cervix.
• Major surgery (major according to the investigator's assessment) performed within 12 weeks prior to randomization or planned during study conduct, e.g. hip replacement.
• Pathological safety lab parameters: haemoglobin < 8 g/dL, total white blood count (WBC) < 3000 cells/μl, neutrophils < 1000 cells/μl, thrombocytes < 100.000/μl, creatinine ≥ 2 mg/dL, total bilirubin > 2 x ULN with ratio of direct/indirect >1 (patients with Gilbert's syndrome are not excluded), Alkaline Phosphatase >3 x ULN.
• Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial
• Previous enrolment in this trial (exception: patients of screening cohort may be enrolled in study cohort)
• Currently enrolled in another investigational device or drug trial
• Women who are pregnant, nursing, or who plan to become pregnant in the trial
• Evidence of a current or previous disease, medical condition (including chronic alcohol or drug abuse) other than Crohn´s disease, surgical procedure, medical examination finding (including vital signs and electrocardiogram (ECG)), or laboratory value at the screening visit outside the reference range that in the opinion of the investigator is clinically significant and would make the study participant unreliable to adhere to the protocol or to complete the trial, compromise the safety of the patient, or compromise the quality of the data
• History of allergy/hypersensitivity to the systemically administered trial medication agent or its excipients or to contrast media

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents. Exceptions might apply, e.g. studies in products where Boehringer Ingelheim is not the license holder; studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; studies conducted in a single center or targeting rare diseases (in case of low number of patients and therefore limitations with anonymization).

For more details refer to: https://www.mystudywindow.com/msw/datatransparency

All subjects who entered the Screening Cohort or the Study Cohort.

Screening cohort: up to 56 days. Period 1: From start of treatment (Placebo or Spesolimab) in period 1 till start of treatment (Placebo or Spesolimab) in period 2, up to 84 days. Period 2: From start of treatment (Placebo or Spesolimab) in period 2 till end of last infusion (Placebo or Spesolimab) in period 2 + residual effect period of 112 days, up to 182 days.

Screening cohort: all patients of the Screening Cohort who entered the trial.

Study cohort: all patients who were randomised and treated with any amount of study drug.

For the primary endpoint, due to the limited number of evaluable samples from the curettage at baseline and at Week 4, curettage biopsies were not included in the gene expression analysis.