Crohn Disease
Conditions
Brief summary
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.
Interventions
DRUGSpesolimab
Spesolimab 1200 milligram intravenously every 4 weeks (week 0, 4, 8, 12, 16 and 20). At week 12 Placebo patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20).
DRUGPlacebo
Placebo intravenously every 4 weeks (week 0, 4, 8). At week 12 achievement of combined perianal fistula remission was determined, patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). Patients with combined perianal fistula remission remained on Placebo and were treated with placebo intravenously every 4 weeks (week 12, 16 and 20).
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Total Number of Deregulated Genes at Week 4 | Biopsies taken at screening (Week -3) and at week 4 of treatment. | The total number of deregulated genes based on biopsies from the inner fistula orifice at Week 4 comparing changes in gene expression from baseline between the two treatment groups. For each gene, a repeated measures linear regression model was utilized with treatment (BI 655130 or Placebo), visit (baseline, week 4), treatment by visit interaction as fixed effect and patient as a blocking factor. Changes will be quantified by log2 fold changes (FC) and associated False Discovery Rate (FDR) adjusted p-values. Genes will be considered deregulated if they fulfil the following criteria: * FDR adjusted p-value ≤ 0.05 * \|fold change\| ≥ 1.5 (\|log2 fold change\| ≥ 0.58) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Perianal Fistula Response at Week 12 | At baseline (day 1) and week 12 (day 85) of treatment. | Number of patients with perianal fistula response at Week 12 defined as closure of at least 50% of external openings, no drainage/discharge despite gentle finger compression of fistulas that were draining at baseline and without new emerging fistulas. The no response imputation (NRI) approach is applied: missing visits where imputed whereby all subsequent visits after a patient took rescue medication for the disease under study or died due to any cause were considered to be missing. |
| Number of Patients With Perianal Fistula Remission at Week 12 | At baseline (day 1) and week 12 (day 85) of treatment. | Proportion of patients with perianal fistula remission at Week 12 defined as closure of all external openings, no drainage/discharge despite gentle finger compression of fistulas that were draining at baseline and without new emerging fistulas. The no response imputation (NRI) approach is applied: missing visits where imputed whereby all subsequent visits after a patient took rescue medication for the disease under study or died due to any cause were considered to be missing. |
| Number of Patients With Combined Perianal Fistula Remission at Week 12 | At baseline (day 1) and week 12 (day 85) of treatment. | Number of patients with combined perianal fistula remission at Week 12 defined as closure of all external openings, no drainage/discharge despite gentle finger compression of fistulas that were draining at baseline and without new emerging fistulas, AND absence collections of \>2 centimeter, confirmed by magnetic resonance imaging (MRI) in at least 2 of 3 dimensions - blinded and centrally read. The no response imputation (NRI) approach is applied: missing visits where imputed whereby all subsequent visits after a patient took rescue medication for the disease under study or died due to any cause were considered to be missing. |
Countries
Austria, Belgium, Denmark, Germany, Hungary, Netherlands, South Korea, Spain
Participant flow
Recruitment details
The trial was divided into a Screening Cohort and a Study Cohort: Screening Cohort did not receive study treatment. Study Cohort was a randomised, double-blind, placebo-controlled, Phase IIa design, and was conducted in 2 periods each of 12 weeks' duration. Patients who completed Week 24 of Period 2 and had clinical benefit were offered continued treatment in an open label, long-term extension study. Patients who did not continue into the extension study were followed up at Week 36.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Screening Cohort Patients enrolled in the Screening Cohort did not receive study treatment. This was a feasibility phase for fistula preparation and seton placement to determine the tissue samples that were suitable for analysis of the primary endpoint in the Study Cohort. | 6 |
| Study Cohort - Placebo Patients with perianal fistulising Crohn's disease received Placebo intravenously every 4 weeks (week 0, 4, 8). At week 12 achievement of combined perianal fistula remission was determined, patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). Patients with combined perianal fistula remission remained on Placebo and were treated with placebo intravenously every 4 weeks (week 12, 16 and 20). | 10 |
| Study Cohort - Spesolimab Patients with perianal fistulising Crohn's disease received Spesolimab 1200 milligram intravenously every 4 weeks (week 0, 4, 8, 12, 16 and 20). At week 12 Placebo patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). | 11 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Study Cohort Period 1 (Week 1 - <week12) | Lack of Efficacy | 0 | 1 | 0 |
| Study Cohort Period 1 (Week 1 - <week12) | Lost to Follow-up | 0 | 0 | 1 |
| Study Cohort Period 1 (Week 1 - <week12) | Withdrawal by Subject | 0 | 0 | 1 |
| Study Cohort - Period 2 (>=Week 12 - 24) | Withdrawal by Subject | 0 | 0 | 1 |
| Study Cohort Week 12 Assignment | Switched to Spesolimab in period 2 | 0 | 4 | 0 |
Baseline characteristics
| Characteristic | Screening Cohort | Study Cohort - Placebo | Study Cohort - Spesolimab | Total |
|---|---|---|---|---|
| Age, Continuous | 42.5 years STANDARD_DEVIATION 10.8 | 34.0 years STANDARD_DEVIATION 8.3 | 39.2 years STANDARD_DEVIATION 10.8 | 38.0 years STANDARD_DEVIATION 10.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 10 Participants | 11 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 8 Participants | 10 Participants | 24 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 9 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 10 | 0 / 11 | 0 / 5 | 0 / 4 | 0 / 9 |
| other Total, other adverse events | 1 / 6 | 9 / 10 | 6 / 11 | 3 / 5 | 4 / 4 | 5 / 9 |
| serious Total, serious adverse events | 0 / 6 | 0 / 10 | 1 / 11 | 1 / 5 | 0 / 4 | 0 / 9 |
Outcome results
Primary
The Total Number of Deregulated Genes at Week 4
The total number of deregulated genes based on biopsies from the inner fistula orifice at Week 4 comparing changes in gene expression from baseline between the two treatment groups. For each gene, a repeated measures linear regression model was utilized with treatment (BI 655130 or Placebo), visit (baseline, week 4), treatment by visit interaction as fixed effect and patient as a blocking factor. Changes will be quantified by log2 fold changes (FC) and associated False Discovery Rate (FDR) adjusted p-values. Genes will be considered deregulated if they fulfil the following criteria: * FDR adjusted p-value ≤ 0.05 * \|fold change\| ≥ 1.5 (\|log2 fold change\| ≥ 0.58)
Time frame: Biopsies taken at screening (Week -3) and at week 4 of treatment.
Population: RNA Sequencing Set: All patients who were randomised and treated with any amount of study drug and who provide a valid baseline and at least one valid post-baseline observation for at least one gene expression variable of biopsy. Data analysed with original results (OR) approach, implying the presentation of data exactly as observed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Cohort - Placebo | The Total Number of Deregulated Genes at Week 4 | 0 Deregulated genes |
| Study Cohort - Spesolimab | The Total Number of Deregulated Genes at Week 4 | 0 Deregulated genes |
Secondary
Number of Patients With Combined Perianal Fistula Remission at Week 12
Number of patients with combined perianal fistula remission at Week 12 defined as closure of all external openings, no drainage/discharge despite gentle finger compression of fistulas that were draining at baseline and without new emerging fistulas, AND absence collections of \>2 centimeter, confirmed by magnetic resonance imaging (MRI) in at least 2 of 3 dimensions - blinded and centrally read. The no response imputation (NRI) approach is applied: missing visits where imputed whereby all subsequent visits after a patient took rescue medication for the disease under study or died due to any cause were considered to be missing.
Time frame: At baseline (day 1) and week 12 (day 85) of treatment.
Population: Includes all patients of the Study Cohort who provided a baseline value and at least one post-baseline value for at least one secondary endpoint or further efficacy endpoint. Following the intent-to-treat principle, patients will be analysed according to the treatment they were assigned to at randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Cohort - Placebo | Number of Patients With Combined Perianal Fistula Remission at Week 12 | 6 Participants |
| Study Cohort - Spesolimab | Number of Patients With Combined Perianal Fistula Remission at Week 12 | 1 Participants |
95% CI: [-0.816, -0.087]
Secondary
Number of Patients With Perianal Fistula Remission at Week 12
Proportion of patients with perianal fistula remission at Week 12 defined as closure of all external openings, no drainage/discharge despite gentle finger compression of fistulas that were draining at baseline and without new emerging fistulas. The no response imputation (NRI) approach is applied: missing visits where imputed whereby all subsequent visits after a patient took rescue medication for the disease under study or died due to any cause were considered to be missing.
Time frame: At baseline (day 1) and week 12 (day 85) of treatment.
Population: Includes all patients of the Study Cohort who provided a baseline value and at least one post-baseline value for at least one secondary endpoint or further efficacy endpoint. Following the intent-to-treat principle, patients will be analysed according to the treatment they were assigned to at randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Cohort - Placebo | Number of Patients With Perianal Fistula Remission at Week 12 | 6 Participants |
| Study Cohort - Spesolimab | Number of Patients With Perianal Fistula Remission at Week 12 | 1 Participants |
95% CI: [-0.816, -0.087]
Secondary
Number of Patients With Perianal Fistula Response at Week 12
Number of patients with perianal fistula response at Week 12 defined as closure of at least 50% of external openings, no drainage/discharge despite gentle finger compression of fistulas that were draining at baseline and without new emerging fistulas. The no response imputation (NRI) approach is applied: missing visits where imputed whereby all subsequent visits after a patient took rescue medication for the disease under study or died due to any cause were considered to be missing.
Time frame: At baseline (day 1) and week 12 (day 85) of treatment.
Population: Includes all patients of the Study Cohort who provided a baseline value and at least one post-baseline value for at least one secondary endpoint or further efficacy endpoint. Following the intent-to-treat principle, patients will be analysed according to the treatment they were assigned to at randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Cohort - Placebo | Number of Patients With Perianal Fistula Response at Week 12 | 7 Participants |
| Study Cohort - Spesolimab | Number of Patients With Perianal Fistula Response at Week 12 | 1 Participants |
95% CI: [-0.88, -0.186]