Colitis, Ulcerative
Conditions
Brief summary
The objectives of this trial are safety and efficacy (proof-of-concept) of induction of mucosal healing by BI 655130 add-on therapy in patients with mild or moderate ulcerative colitis and persisting endoscopic activity despite pre-existing TNFi treatment. This trial will explore safety and efficacy of a dose of BI 655130 that was modelled to achieve the similar exposures as the highest exposures tested and found safe and tolerable in preceding single and multiple dose studies in healthy subjects, as add-on to pre-existing TNFi (Tumor necrosis factor inhibitor) treatment. Secondary and further objectives include assessment of the pharmacokinetic (PK) profile of BI 655130 and early exploration of specific biomarkers with potential usefulness to predict clinical efficacy or safety outcome or help understand BI 655130's mode of action.
Interventions
DRUGSpesolimab
12 weeks treatment
DRUGPlacebo
12 weeks treatment
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 screening and randomisation * Diagnosis of ulcerative colitis \>= 5 months prior to screening * Receiving TNFi treatment with doses (i.e. dose and dosing interval) unchanged for \>= 4 months (Infliximab) or \>= 2 Monaten (Adalimumab or Golimumab) prior to randomisation * Mild or moderate disease activity, defined as total Mayo Score (MCS) (\<= 10) * Further inclusion criteria apply
Exclusion criteria
* Prior use of more than two different TNF inhibitors or vedolizumab * Extensive colonic resection * Evidence of infection with C. difficile or other intestinal pathogen \<28 days prior to screening * Active or latent tuberculosis * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Endoscopic Improvement (MCS mESS ≤1) at Week 12 | At Week 12 | Proportion of participants with endoscopic improvement (Mayo clinical score (MCS) modified endoscopic sub-score (mESS) ≤1) at Week 12 was reported. The endoscopic improvement (mucosal healing) was defined as the Mayo clinical score (MCS) modified endoscopic sub-score (mESS) ≤ 1 point. The MCS mESS ranged from 0 (normal) to 3 (severe disease). The mESS was assessed by a central reader who was independent from the investigator. The 95% confidence intervals (in the descriptive statistics part) were calculated using the method of Wilson. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Total Clinical Remission (tCR) Based on Total Mayo Clinical Score at Week 12 | At Week 12 | Proportion of participants with total clinical remission based on total Mayo clinical score at Week 12 was reported. The total clinical remission based on total Mayo clinical score was defined as the total Mayo clinical score ≤ 2 points and all sub-scores ≤ 1 point. The total Mayo clinical score was a composite disease activity score consisting of 4 sub-scores: stool frequency, rectal bleeding, physician's global assessment, and modified endoscopic appearance. Each sub-score ranged from 0 (normal) to 3 (severe disease/worse disease status). The total Mayo score was by summing up the four sub-scores and ranged from 0 to 12 with higher score indicating worse disease. The 95% confidence intervals (in the descriptive statistics part) were calculated using the method of Wilson. |
| Proportion of Participants With Histological Remission at Week 12 | At Week 12 | Proportion of participants with histological remission at Week 12 was reported. The histological remission was defined as the Robarts histology index score ≤ 6. The Robarts histopathology index (RHI) was a histologic activity score, scoring the components chronic inflammatory infiltrate, lamina propria neutrophils, neutrophils in epithelium and erosion or ulceration on a scale of 0 to 3. The 4 components were weighted differently to calculate the RHI, with RHI = 1 × chronic inflammatory infiltrate level + 2 × lamina propria neutrophils + 3 × neutrophils in epithelium + 5 × erosion or ulceration. The resulting RHI score ranged from 0 (no disease activity) to 33 (severe disease activity). The 95% confidence intervals (in descriptive statistics part) were calculated using the method of Wilson. |
| Proportion of Participants With Clinical Remission (CR) Based on Mayo Clinical Score at Week 12 | At Week 12 | Proportion of participants with clinical remission (CR) based on Mayo clinical score at Week 12 was reported. The clinical remission based on Mayo clinical score was defined as the total Mayo clinical Score ≤ 2 and Rectal Bleeding Subscore = 0, Stool Frequency Score =0 or 1 and drop ≥ 1 from baseline, and Modified endoscopic sub-score (mESS) ≤ 1. The total Mayo clinical score was a composite disease activity score consisting of 4 sub-scores: stool frequency, rectal bleeding, physician's global assessment, and modified endoscopic appearance. Each sub-score ranged from 0 (normal) to 3 (severe disease/worse disease status). The total Mayo clinical score was by summing up the four sub-scores and ranged from 0 to 12 with higher score indicating worse disease. The 95% confidence intervals (in the descriptive statistics part) were calculated using the method of Wilson. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From first does of study medication until end of the follow-up period, up to 36 weeks. | Number of participants with any treatment-emergent adverse events (TEAEs) was reported. |
Countries
Denmark, Germany, Netherlands, Norway, Spain, United Kingdom
Participant flow
Recruitment details
This randomized, placebo-controlled, double-blind, parallel-group trial over 36 weeks, including a 24-week follow-up period evaluated safety and efficacy of induction of mucosal healing by Spesolimab (BI 655130) add-on therapy in patients with mild or moderate ulcerative colitis and persisting endoscopic activity despite pre-existing tumor necrosis factor inhibitor treatment.
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 |
|---|---|
| Placebo - Randomized Matching placebo was administered via intravenous infusion over 12 weeks of treatment.
Participants who were randomized into the Placebo treatment were included in this arm. | 8 |
| Spesolimab 1200 mg - Randomized 1200 milligrams (mg) of Spesolimab (BI 655130) were administered every 4 weeks (q4w) via intravenous infusion over 12 weeks of treatment (3 injections of Spesolimab 1200 mg in total during the 12 weeks: at Week 0, 4, and 8 respectively).
Participants who were randomized into the Spesolimab 1200 mg treatment were included in this arm. | 14 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo - Randomized | Spesolimab 1200 mg - Randomized | Total |
|---|---|---|---|
| Age, Continuous | 45.5 Years STANDARD_DEVIATION 12.1 | 43.1 Years STANDARD_DEVIATION 9.9 | 44.0 Years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 14 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Mayo clinical score (MCS) modified endoscopic subscore (mESS) | 2.8 Score on a scale STANDARD_DEVIATION 0.5 | 2.8 Score on a scale STANDARD_DEVIATION 0.4 | 2.8 Score on a scale STANDARD_DEVIATION 0.4 |
| Number of participants per Mayo clinical score modified endoscopic subscore value group 0 | 0 Participants | 0 Participants | 0 Participants |
| Number of participants per Mayo clinical score modified endoscopic subscore value group 1 | 0 Participants | 0 Participants | 0 Participants |
| Number of participants per Mayo clinical score modified endoscopic subscore value group 2 | 2 Participants | 3 Participants | 5 Participants |
| Number of participants per Mayo clinical score modified endoscopic subscore value group 3 | 6 Participants | 11 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 13 Participants | 21 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 15 |
| other Total, other adverse events | 6 / 7 | 15 / 15 |
| serious Total, serious adverse events | 1 / 7 | 2 / 15 |
Outcome results
Primary
Proportion of Participants With Endoscopic Improvement (MCS mESS ≤1) at Week 12
Proportion of participants with endoscopic improvement (Mayo clinical score (MCS) modified endoscopic sub-score (mESS) ≤1) at Week 12 was reported. The endoscopic improvement (mucosal healing) was defined as the Mayo clinical score (MCS) modified endoscopic sub-score (mESS) ≤ 1 point. The MCS mESS ranged from 0 (normal) to 3 (severe disease). The mESS was assessed by a central reader who was independent from the investigator. The 95% confidence intervals (in the descriptive statistics part) were calculated using the method of Wilson.
Time frame: At Week 12
Population: Full analysis set (FAS): This patient set includes all patients in the safety analysis set who had a baseline measurement available for the primary endpoint. Treatment assignment will be as randomized. Patients who were randomized but not treated were excluded from the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo - Randomized | Proportion of Participants With Endoscopic Improvement (MCS mESS ≤1) at Week 12 | 0.375 Proportion of participants |
| Spesolimab 1200 mg - Randomized | Proportion of Participants With Endoscopic Improvement (MCS mESS ≤1) at Week 12 | 0.143 Proportion of participants |
95% CI: [-0.568, 0.118]
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Number of participants with any treatment-emergent adverse events (TEAEs) was reported.
Time frame: From first does of study medication until end of the follow-up period, up to 36 weeks.
Population: Safety Analysis Set (SAF): this patient set included all randomized patients who received at least one dose of trial drug. Treatment assignment was analyzed according to the actual treatment. 1 patient who was assigned to placebo accidentally received one dose of Spesolimab and was analyzed in the Spesolimab group in the SAF.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo - Randomized | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 6 Participants |
| Spesolimab 1200 mg - Randomized | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 15 Participants |
Secondary
Proportion of Participants With Clinical Remission (CR) Based on Mayo Clinical Score at Week 12
Proportion of participants with clinical remission (CR) based on Mayo clinical score at Week 12 was reported. The clinical remission based on Mayo clinical score was defined as the total Mayo clinical Score ≤ 2 and Rectal Bleeding Subscore = 0, Stool Frequency Score =0 or 1 and drop ≥ 1 from baseline, and Modified endoscopic sub-score (mESS) ≤ 1. The total Mayo clinical score was a composite disease activity score consisting of 4 sub-scores: stool frequency, rectal bleeding, physician's global assessment, and modified endoscopic appearance. Each sub-score ranged from 0 (normal) to 3 (severe disease/worse disease status). The total Mayo clinical score was by summing up the four sub-scores and ranged from 0 to 12 with higher score indicating worse disease. The 95% confidence intervals (in the descriptive statistics part) were calculated using the method of Wilson.
Time frame: At Week 12
Population: Full analysis set (FAS): This patient set includes all patients in the safety analysis set who had a baseline measurement available for the primary endpoint. Treatment assignment will be as randomized. Patients who were randomized but not treated were excluded from the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo - Randomized | Proportion of Participants With Clinical Remission (CR) Based on Mayo Clinical Score at Week 12 | 0.000 Proportion of participants |
| Spesolimab 1200 mg - Randomized | Proportion of Participants With Clinical Remission (CR) Based on Mayo Clinical Score at Week 12 | 0.143 Proportion of participants |
95% CI: [-0.197, 0.399]
Secondary
Proportion of Participants With Histological Remission at Week 12
Proportion of participants with histological remission at Week 12 was reported. The histological remission was defined as the Robarts histology index score ≤ 6. The Robarts histopathology index (RHI) was a histologic activity score, scoring the components chronic inflammatory infiltrate, lamina propria neutrophils, neutrophils in epithelium and erosion or ulceration on a scale of 0 to 3. The 4 components were weighted differently to calculate the RHI, with RHI = 1 × chronic inflammatory infiltrate level + 2 × lamina propria neutrophils + 3 × neutrophils in epithelium + 5 × erosion or ulceration. The resulting RHI score ranged from 0 (no disease activity) to 33 (severe disease activity). The 95% confidence intervals (in descriptive statistics part) were calculated using the method of Wilson.
Time frame: At Week 12
Population: Full analysis set (FAS): This patient set includes all patients in the safety analysis set who had a baseline measurement available for the primary endpoint. Treatment assignment will be as randomized. Patients who were randomized but not treated were excluded from the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo - Randomized | Proportion of Participants With Histological Remission at Week 12 | 0.500 Proportion of participants |
| Spesolimab 1200 mg - Randomized | Proportion of Participants With Histological Remission at Week 12 | 0.214 Proportion of participants |
95% CI: [-0.602, 0.101]
Secondary
Proportion of Participants With Total Clinical Remission (tCR) Based on Total Mayo Clinical Score at Week 12
Proportion of participants with total clinical remission based on total Mayo clinical score at Week 12 was reported. The total clinical remission based on total Mayo clinical score was defined as the total Mayo clinical score ≤ 2 points and all sub-scores ≤ 1 point. The total Mayo clinical score was a composite disease activity score consisting of 4 sub-scores: stool frequency, rectal bleeding, physician's global assessment, and modified endoscopic appearance. Each sub-score ranged from 0 (normal) to 3 (severe disease/worse disease status). The total Mayo score was by summing up the four sub-scores and ranged from 0 to 12 with higher score indicating worse disease. The 95% confidence intervals (in the descriptive statistics part) were calculated using the method of Wilson.
Time frame: At Week 12
Population: Full analysis set (FAS): This patient set includes all patients in the safety analysis set who had a baseline measurement available for the primary endpoint. Treatment assignment will be as randomized. Patients who were randomized but not treated were excluded from the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo - Randomized | Proportion of Participants With Total Clinical Remission (tCR) Based on Total Mayo Clinical Score at Week 12 | 0.125 Proportion of participants |
| Spesolimab 1200 mg - Randomized | Proportion of Participants With Total Clinical Remission (tCR) Based on Total Mayo Clinical Score at Week 12 | 0.071 Proportion of participants |
95% CI: [-0.404, 0.21]