Colitis, Ulcerative
Conditions
Brief summary
This trial has two sequentially enrolling parts with different objectives. The primary objectives of this trial are * to prove the concept of clinical activity of BI655130 (SPESOLIMAB) in patients with moderate-to-severely active ulcerative colitis who have failed previous biologic treatments and to identify efficacious and safe dose regimens in Part 1 (Phase II) * to confirm efficacy and safety of BI655130 (SPESOLIMAB) in patients with moderate-to-severely active ulcerative colitis who have failed previous biologic treatments in Part 2 (Phase III) * To provide, along with induction study 1368-0018 and the run-in cohort of 1368-0020, the target population to be evaluated in study 1368-0020.
Interventions
DRUGSpesolimab
Solution for infusion
DRUGPlacebo
Solution for infusion
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, males or females * Diagnosis of ulcerative colitis ≥ 3 months prior to screening by clinical and endoscopic evidence corroborated by a histopathology report * Moderate to severe activity (total MCS 6 to 12 with a RBS ≥ 1 AND an SFS ≥ 1 AND mESS ≥ 2 within 7-28 days prior to first dose) * Endoscopic activity extending proximal to the rectum (≥ 15 cm from anal verge) * Well-documented demonstration of inadequate response or loss of response or have had unacceptable side effects with approved doses of TNFɑ antagonists (infliximab, adalimumab, golimumab) and/or vedolizumab in the past (screening of both TNFɑ antagonists-AND-Vedolizumab failure patients will be capped once 48 randomized patients in Part 1 and 117 randomized patients in Part 2 meet this criterion; patients who have already been screened at the time of the cap will continue to be randomized into the study) * Further inclusion criteria apply
Exclusion criteria
* Evidence of abdominal abscess at screening * Evidence of fulminant colitis or toxic megacolon at screening * Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Clinical Remission at Week 12 | At week 12. | Proportion of patients with clinical remission (defined as modified Mayo Clinical Score (MCS) ≤ 2, with Stool Frequency Score (SFS) = 0 or 1 \[if drop ≥1 from baseline\] and Rectal Bleeding Score (RBS) = 0 and modified Endoscopic Subscore (mESS) ≤ 1) at week 12. Proportion of patients was calculated as n/N, with n=number of patients with clinical remission at week 12 and N=number analyzed. 95% Confidence Intervals (CI) were calculated using the method of Wilson. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Clinical Response at Week 12 | At week 12. | Proportion of patients with clinical response (defined as Rectal Bleeding Score (RBS) ≤ 1 or decrease by ≥1 from baseline; and total Mayo Clinical Score (MCS) decrease by ≥ 3 and 30% from baseline) at week 12. Proportion of patients is calculated as n/N, with n=number of patients with clinical response at week 12 and N=number of patients analyzed. 95% Confidence Intervals (CI) are calculated using the method of Wilson. |
| Proportion of Patients With Endoscopic Improvement at Week 12 | At week 12. | Proportion of patients with endoscopic improvement at week 12 (defined as modified Endoscopic Subscore (mESS) ≤ 1) Proportion of patients was calculated as n/N, with n=number of patients with Endoscopic Improvment at Week 12 and N=number analysed. 95% Confidence Intervals (CI) were calculated using the method of Wilson. |
| Proportion of Patients With Combined Endoscopic Improvement and Histologic Remission at Week 12 | At week 12. | Proportion of patients with combined endoscopic improvement and histologic remission at week 12 (defined as modified Endoscopic Subscore (mESS) ≤ 1 and Robarts Histology Index ≤ 6). Proportion of patients was calculated as n/N, with n= number of patients with Endoscopic Improvement and histologic remission at week 12 and N=number of patients analysed. |
| Change in Inflammatory Bowel Disease Questionnaire (IBDQ) Score From Baseline at Week 12 | At baseline and at week 12. | Change in Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline at Week 12. The IBDQ is a 32-item self-report questionnaire for patients with IBD to evaluate the patient reported outcomes across 4 dimensions: bowel symptoms (loose stools, abdominal pain), systemic symptoms (fatigue, altered sleep pattern), social function (work attendance, need to cancel social events), and emotional function (anger, depression, irritability). The response options describe the magnitude or frequency of impairment from 1 (most severe) to 7 (no impairment). The items are summed up, resulting in a sum score ranging from 32 to 224 points, with higher scores indicating better outcomes. A score change of 16 is reported to reflect the minimal clinically important difference (MCID). Mean is adjusted mean. |
Countries
Austria, Belgium, Canada, Germany, Italy, Japan, Poland, Russia, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Phase II/III randomized, placebo-controlled, double-blind trial to assess the safety and efficacy of spesolimab induction therapy in patients with moderate-to-severely active ulcerative colitis who have failed previous biologics therapy. Phase III was not conducted, due to recruitment issues in Phase II.
Pre-assignment details
Only subjects that met all the study inclusion and non of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
Participants by arm
| Arm | Count |
|---|---|
| Placebo A solution of placebo was administered as intravenous infusion once every 4 weeks over a period of 12 weeks, (at week 0, week 4, week 8) in patients with moderate to severe ulcerative colitis who had failed previous biological treatments in the past. | 23 |
| 300 mg Spesolimab (BI 655130) SD A single dose (SD) of 300 milligram (mg) solution of spesolimab was administered as intravenous infusion at week 0 in patients with moderate to severe ulcerative colitis who had failed previous biological treatments in the past. | 24 |
| 450 mg Spesolimab (BI 655130) q4w 450 mg solution of spesolimab was administered, as intravenous infusion, once every 4 weeks (q4w) over a period of 12 weeks, (at week 0, week 4, week 8) in patients with moderate to severe ulcerative colitis who had failed previous biological treatments in the past. | 23 |
| 1200 mg Spesolimab (BI 655130) q4w 1200 mg solution of spesolimab was administered, as intravenous infusion, once every 4 weeks (q4w) over a period of 12 weeks, (at week 0, week 4, week 8) in patients with moderate to severe ulcerative colitis who had failed previous biological treatments in the past. | 28 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 0 | 3 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 | 3 |
| Overall Study | Not treated | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 | 1 |
| Overall Study | Withdrawn by Principle Investigator | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | 1200 mg Spesolimab (BI 655130) q4w | 450 mg Spesolimab (BI 655130) q4w | 300 mg Spesolimab (BI 655130) SD |
|---|---|---|---|---|---|
| Age, Continuous | 42.2 Years STANDARD_DEVIATION 14.1 | 42.5 Years STANDARD_DEVIATION 14.6 | 43.9 Years STANDARD_DEVIATION 14.9 | 42.3 Years STANDARD_DEVIATION 15.3 | 41.4 Years STANDARD_DEVIATION 14.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 97 Participants | 27 Participants | 23 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 14 Participants | 5 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 80 Participants | 21 Participants | 18 Participants | 23 Participants |
| Sex: Female, Male Female | 11 Participants | 36 Participants | 8 Participants | 10 Participants | 7 Participants |
| Sex: Female, Male Male | 12 Participants | 62 Participants | 20 Participants | 13 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 24 | 0 / 23 | 0 / 27 |
| other Total, other adverse events | 5 / 23 | 7 / 24 | 7 / 23 | 17 / 27 |
| serious Total, serious adverse events | 4 / 23 | 3 / 24 | 2 / 23 | 3 / 27 |
Outcome results
Primary
Proportion of Patients With Clinical Remission at Week 12
Proportion of patients with clinical remission (defined as modified Mayo Clinical Score (MCS) ≤ 2, with Stool Frequency Score (SFS) = 0 or 1 \[if drop ≥1 from baseline\] and Rectal Bleeding Score (RBS) = 0 and modified Endoscopic Subscore (mESS) ≤ 1) at week 12. Proportion of patients was calculated as n/N, with n=number of patients with clinical remission at week 12 and N=number analyzed. 95% Confidence Intervals (CI) were calculated using the method of Wilson.
Time frame: At week 12.
Population: Randomised Set - Non Response Imputation (RS-NRI): The randomised set included all randomised patients, including patients with non-response imputation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Patients With Clinical Remission at Week 12 | 0.00 Proportion of Participants |
| 300 mg Spesolimab (BI 655130) SD | Proportion of Patients With Clinical Remission at Week 12 | 0.042 Proportion of Participants |
| 450 mg Spesolimab (BI 655130) q4w | Proportion of Patients With Clinical Remission at Week 12 | 0.087 Proportion of Participants |
| 1200 mg Spesolimab (BI 655130) q4w | Proportion of Patients With Clinical Remission at Week 12 | 0.071 Proportion of Participants |
95% CI: [-0.105, 0.202]
95% CI: [-0.069, 0.268]
95% CI: [-0.081, 0.226]
Secondary
Change in Inflammatory Bowel Disease Questionnaire (IBDQ) Score From Baseline at Week 12
Change in Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline at Week 12. The IBDQ is a 32-item self-report questionnaire for patients with IBD to evaluate the patient reported outcomes across 4 dimensions: bowel symptoms (loose stools, abdominal pain), systemic symptoms (fatigue, altered sleep pattern), social function (work attendance, need to cancel social events), and emotional function (anger, depression, irritability). The response options describe the magnitude or frequency of impairment from 1 (most severe) to 7 (no impairment). The items are summed up, resulting in a sum score ranging from 32 to 224 points, with higher scores indicating better outcomes. A score change of 16 is reported to reflect the minimal clinically important difference (MCID). Mean is adjusted mean.
Time frame: At baseline and at week 12.
Population: Modified Randomised Set (m-RS): The m-RS included all patients in the RS who had a baseline and at least 1 post-baseline measurement for the endpoint under consideration. Treatment assignment was randomised.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Inflammatory Bowel Disease Questionnaire (IBDQ) Score From Baseline at Week 12 | 19.8 Score on a scale |
| 300 mg Spesolimab (BI 655130) SD | Change in Inflammatory Bowel Disease Questionnaire (IBDQ) Score From Baseline at Week 12 | 19.5 Score on a scale |
| 450 mg Spesolimab (BI 655130) q4w | Change in Inflammatory Bowel Disease Questionnaire (IBDQ) Score From Baseline at Week 12 | 21.2 Score on a scale |
| 1200 mg Spesolimab (BI 655130) q4w | Change in Inflammatory Bowel Disease Questionnaire (IBDQ) Score From Baseline at Week 12 | 20.8 Score on a scale |
Comparison: Restricted maximum likelihood (REML)-based repeated measures approach. The model included fixed, categorical effects of treatment, visit, and treatment by visit interaction, and stratification factors (prior biologic treatment failure and concomitant corticosteroid therapy at Visit 2/randomisation), as well as the continuous fixed covariates of baseline and baseline-by-visit interaction. An unstructured covariance structure was used to model the within-patient measurements.p-value: 0.977695% CI: [-21.6, 21]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based repeated measures approach. The model included fixed, categorical effects of treatment, visit, and treatment by visit interaction, and stratification factors (prior biologic treatment failure and concomitant corticosteroid therapy at Visit 2/randomisation), as well as the continuous fixed covariates of baseline and baseline-by-visit interaction. An unstructured covariance structure was used to model the within-patient measurements.p-value: 0.89495% CI: [-19.6, 22.4]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based repeated measures approach. The model included fixed, categorical effects of treatment, visit, and treatment by visit interaction, and stratification factors (prior biologic treatment failure and concomitant corticosteroid therapy at Visit 2/randomisation), as well as the continuous fixed covariates of baseline and baseline-by-visit interaction. An unstructured covariance structure was used to model the within-patient measurementsp-value: 0.924195% CI: [-20, 22.1]Mixed Models Analysis
Secondary
Proportion of Patients With Clinical Response at Week 12
Proportion of patients with clinical response (defined as Rectal Bleeding Score (RBS) ≤ 1 or decrease by ≥1 from baseline; and total Mayo Clinical Score (MCS) decrease by ≥ 3 and 30% from baseline) at week 12. Proportion of patients is calculated as n/N, with n=number of patients with clinical response at week 12 and N=number of patients analyzed. 95% Confidence Intervals (CI) are calculated using the method of Wilson.
Time frame: At week 12.
Population: Randomised Set - Non Response Imputation (RS-NRI): The randomised set included all randomised patients, including patients with non-response imputation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Patients With Clinical Response at Week 12 | 0.217 Proportion of participants |
| 300 mg Spesolimab (BI 655130) SD | Proportion of Patients With Clinical Response at Week 12 | 0.167 Proportion of participants |
| 450 mg Spesolimab (BI 655130) q4w | Proportion of Patients With Clinical Response at Week 12 | 0.261 Proportion of participants |
| 1200 mg Spesolimab (BI 655130) q4w | Proportion of Patients With Clinical Response at Week 12 | 0.250 Proportion of participants |
95% CI: [-0.276, 0.176]
95% CI: [-0.199, 0.28]
95% CI: [-0.204, 0.252]
Secondary
Proportion of Patients With Combined Endoscopic Improvement and Histologic Remission at Week 12
Proportion of patients with combined endoscopic improvement and histologic remission at week 12 (defined as modified Endoscopic Subscore (mESS) ≤ 1 and Robarts Histology Index ≤ 6). Proportion of patients was calculated as n/N, with n= number of patients with Endoscopic Improvement and histologic remission at week 12 and N=number of patients analysed.
Time frame: At week 12.
Population: Randomised Set - Non Response Imputation (RS-NRI): The randomised set included all randomised patients, including patients with non-response imputation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Patients With Combined Endoscopic Improvement and Histologic Remission at Week 12 | 0.00 Proportion of participants |
| 300 mg Spesolimab (BI 655130) SD | Proportion of Patients With Combined Endoscopic Improvement and Histologic Remission at Week 12 | 0.083 Proportion of participants |
| 450 mg Spesolimab (BI 655130) q4w | Proportion of Patients With Combined Endoscopic Improvement and Histologic Remission at Week 12 | 0.043 Proportion of participants |
| 1200 mg Spesolimab (BI 655130) q4w | Proportion of Patients With Combined Endoscopic Improvement and Histologic Remission at Week 12 | 0.036 Proportion of participants |
95% CI: [-0.072, 0.258]
95% CI: [-0.104, 0.21]
95% CI: [-0.11, 0.177]
Secondary
Proportion of Patients With Endoscopic Improvement at Week 12
Proportion of patients with endoscopic improvement at week 12 (defined as modified Endoscopic Subscore (mESS) ≤ 1) Proportion of patients was calculated as n/N, with n=number of patients with Endoscopic Improvment at Week 12 and N=number analysed. 95% Confidence Intervals (CI) were calculated using the method of Wilson.
Time frame: At week 12.
Population: Randomised Set - Non Response Imputation (RS-NRI): The randomised set included all randomised patients, including patients with non-response imputation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Patients With Endoscopic Improvement at Week 12 | 0.000 Proportion of participants |
| 300 mg Spesolimab (BI 655130) SD | Proportion of Patients With Endoscopic Improvement at Week 12 | 0.083 Proportion of participants |
| 450 mg Spesolimab (BI 655130) q4w | Proportion of Patients With Endoscopic Improvement at Week 12 | 0.087 Proportion of participants |
| 1200 mg Spesolimab (BI 655130) q4w | Proportion of Patients With Endoscopic Improvement at Week 12 | 0.071 Proportion of participants |
95% CI: [-0.072, 0.258]
95% CI: [-0.069, 0.268]
95% CI: [-0.081, 0.226]