Ulcerative Colitis
Conditions
Brief summary
The purpose of this study is to determine whether etrasimod is a safe and effective treatment for ulcerative colitis.
Interventions
DRUGEtrasimod
DRUGPlacebo
Sponsors
Arena Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Moderately to severely active ulcerative colitis defined as a 3-component Mayo Clinic score * Evidence of colonic ulcerative colitis activity on endoscopy
Exclusion criteria
* Within 30 days prior to randomization, receipt of any of the following for the treatment of underlying disease: Non-biologic therapies (eg, cyclosporine, tacrolimus, tofacitinib, thalidomide), a non-biologic investigational therapy or an approved non-biologic therapy in an investigational protocol * Within 60 days prior to randomization, receipt of any of the following: Infliximab, adalimumab, golimumab, certolizumab, vedolizumab, any other investigational or approved biologic agent * Any prior exposure to natalizumab, efalizumab, or rituximab
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Adapted Mayo Score (MCS) at Week 12 | Baseline and Week 12 | The adapted MCS was used to measure disease activity of ulcerative colitis. It consisted of 3 subscores (stool frequency, rectal bleeding, and findings of endoscopy), each of which was rated on a scale from 0 to 3, indicating normal to severe. The adapted MCS was calculated as the sum of the 3 subscores, and the overall score values ranged from 0 to 9, with a higher score indicating more severe disease. Multiple imputation method was used to handle missing data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-component MCS at Week 12 | Baseline and Week 12 | The 2-component MCS was used to measure disease activity of ulcerative colitis. It consisted of 2 subscores (rectal bleeding and findings on endoscopy), each of which was rated on a scale from 0 to 3, indicating normal to severe. The 2-component MCS was calculated as the sum of the 2 subscores, and the overall score value ranged from 0 to 6, with a higher score indicating more severe disease. Multiple imputation method was used to handle missing data. |
| Change From Baseline in Total Mayo Score (TMS) at Week 12 | Baseline and Week 12 | The TMS was used to measure disease activity of ulcerative colitis. It consisted of 4 subscores \[stool frequency, rectal bleeding, findings of endoscopy (flexible proctosigmoidoscopy), and Physician's Global Assessment (PGA) score\], each of which was rated on a scale from 0 to 3, indicating normal to severe. The TMS was calculated as the sum of the 4 subscores, and the overall score values ranged from 0 to 12, with a higher score indicating more severe disease. Multiple imputation method was used to handle missing data. |
| Percentage of Participants Who Achieved Endoscopic Improvement at Week 12 | Week 12 | For determination of the endoscopic subscore of the MCS, a flexible proctosigmoidoscopy, performed with a videoendoscope following a cleansing prep (oral or rectal cathartic) was performed at screening (within 10 days prior to administration of the first dose of study drug) and the Week 12 visit. This efficacy procedure assessed endoscopic mucosal appearance. The results were rated on a scale from 0 to 3, indicating normal to severe. Endoscopic improvement was defined as Mayo endoscopic subscore (using findings of flexible proctosigmoidoscopy) of ≤1 point. Multiple imputation method was used to handle missing data. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Trichotomous Composite Score of Clinical Remission and Clinical Response at Week 12 | Week 12 | The trichotomous composite score of clinical remission and clinical response at Week 12 is an ordinal categorical endpoint with 3 categories (score ranging 0 to 2: score 2 for achieving both clinical remission and clinical response; 1 for only achieving clinical response, and 0 for achieving neither). Multiple imputation method was used to handle missing data. |
| Percentage of Participants Who Achieved Clinical Remission at Week 12 | Week 12 | A participant was considered to have achieved clinical remission if he/she had: 1) an endoscopy score using flexible proctosigmoidoscopy of 0 or 1 (excluding friability), 2) a rectal bleeding score of 0 or 1, and 3) a stool frequency score of 0 or 1 with a decrease of ≥1 point from baseline. Multiple imputation method was used to handle missing data. |
| Percentage of Participants Who Achieved Clinical Response at Week 12 | Week 12 | A participant was considered to have achieved clinical response if he/she met the criteria of clinical remission defined above, or met criteria of clinical response. Clinical response was defined as a decrease in the adapted MCS of ≥ 2 points and a decrease of ≥ 30% with either a decrease of rectal bleeding of ≥ 1 or rectal bleeding score of 0 or 1. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Czechia, France, Germany, Hungary, Israel, Latvia, Lithuania, New Zealand, Poland, Romania, Russia, South Korea, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study included a screening period (up to 28 days), a double-blind induction treatment period (12 weeks), and a possible follow-up visit (2 weeks after the last study visit). The target population consisted of male or female participants aged between 18 and 80 years (inclusive), with moderately to severely active Ulcerative Colitis.
Pre-assignment details
During the screening period (Days -28 to -1), participants were evaluated for study entry based on the inclusion and exclusion criteria. Screening procedures to evaluate participant eligibility for the study were to be conducted within 28 days prior to study drug administration on Day 1.
Participants by arm
| Arm | Count |
|---|---|
| Etrasimod 1 mg Etrasimod 1 mg was administered orally once daily for 12 weeks, administered with approximately 240 mL (8 ounces) of water. The study drug was to be taken on an empty stomach after an overnight fast of approximately 8 hours. | 52 |
| Etrasimod 2 mg Etrasimod 2 mg was administered orally once daily for 12 weeks, administered with approximately 240 mL (8 ounces) of water. The study drug was to be taken on an empty stomach after an overnight fast of approximately 8 hours. | 50 |
| Placebo Placebo was administered orally once daily for 12 weeks, administered with approximately 240 mL (8 ounces) of water. Placebo was to be taken on an empty stomach after an overnight fast of approximately 8 hours. | 54 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Sponsor Decision | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 5 |
Baseline characteristics
| Characteristic | Etrasimod 1 mg | Etrasimod 2 mg | Placebo | Total |
|---|---|---|---|---|
| Adapted Mayo Score (MCS) | 6.5 score on a scale STANDARD_DEVIATION 1.23 | 6.6 score on a scale STANDARD_DEVIATION 1.17 | 6.5 score on a scale STANDARD_DEVIATION 1.51 | 6.5 score on a scale STANDARD_DEVIATION 1.31 |
| Age, Continuous | 44.0 years | 38.5 years | 46.0 years | 42 years |
| Age, Customized Adults (18-64 years) | 52 Subjects | 49 Subjects | 49 Subjects | 150 Subjects |
| Age, Customized From 65-80 years | 0 Subjects | 1 Subjects | 5 Subjects | 6 Subjects |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 49 Participants | 51 Participants | 149 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 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 | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 47 Participants | 49 Participants | 51 Participants | 147 Participants |
| Sex: Female, Male Female | 22 Participants | 23 Participants | 22 Participants | 67 Participants |
| Sex: Female, Male Male | 30 Participants | 27 Participants | 32 Participants | 89 Participants |
| The 2-component MCS | 4.2 score on a scale STANDARD_DEVIATION 0.75 | 4.2 score on a scale STANDARD_DEVIATION 0.75 | 4.2 score on a scale STANDARD_DEVIATION 0.91 | 4.2 score on a scale STANDARD_DEVIATION 0.8 |
| Total Mayo Score (TMS) | 8.8 score on a scale STANDARD_DEVIATION 1.43 | 8.9 score on a scale STANDARD_DEVIATION 1.47 | 8.7 score on a scale STANDARD_DEVIATION 1.72 | 8.8 score on a scale STANDARD_DEVIATION 1.54 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 52 | 0 / 50 | 0 / 54 |
| other Total, other adverse events | 11 / 52 | 11 / 50 | 9 / 54 |
| serious Total, serious adverse events | 3 / 52 | 0 / 50 | 6 / 54 |
Outcome results
Primary
Change From Baseline in Adapted Mayo Score (MCS) at Week 12
The adapted MCS was used to measure disease activity of ulcerative colitis. It consisted of 3 subscores (stool frequency, rectal bleeding, and findings of endoscopy), each of which was rated on a scale from 0 to 3, indicating normal to severe. The adapted MCS was calculated as the sum of the 3 subscores, and the overall score values ranged from 0 to 9, with a higher score indicating more severe disease. Multiple imputation method was used to handle missing data.
Time frame: Baseline and Week 12
Population: The analysis was performed using the intent-to-treat (ITT) population that consisted of all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etrasimod 1 mg | Change From Baseline in Adapted Mayo Score (MCS) at Week 12 | -1.94 score on a scale |
| Etrasimod 2 mg | Change From Baseline in Adapted Mayo Score (MCS) at Week 12 | -2.49 score on a scale |
| Placebo | Change From Baseline in Adapted Mayo Score (MCS) at Week 12 | -1.50 score on a scale |
Comparison: The primary comparison in the study was between etrasimod 2 mg versus placebo.p-value: =0.009190% CI: [-1.68, -0.3]ANCOVA
p-value: =0.145790% CI: [-1.11, 0.24]ANCOVA
Secondary
Change From Baseline in 2-component MCS at Week 12
The 2-component MCS was used to measure disease activity of ulcerative colitis. It consisted of 2 subscores (rectal bleeding and findings on endoscopy), each of which was rated on a scale from 0 to 3, indicating normal to severe. The 2-component MCS was calculated as the sum of the 2 subscores, and the overall score value ranged from 0 to 6, with a higher score indicating more severe disease. Multiple imputation method was used to handle missing data.
Time frame: Baseline and Week 12
Population: The analysis was performed using the ITT population that consisted of all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etrasimod 1 mg | Change From Baseline in 2-component MCS at Week 12 | -1.30 score on a scale |
| Etrasimod 2 mg | Change From Baseline in 2-component MCS at Week 12 | -1.75 score on a scale |
| Placebo | Change From Baseline in 2-component MCS at Week 12 | -0.92 score on a scale |
Comparison: The primary comparison in the study was between etrasimod 2 mg versus placebo.p-value: =0.00290% CI: [-1.32, -0.36]ANCOVA
p-value: =0.085890% CI: [-0.85, 0.08]ANCOVA
Secondary
Change From Baseline in Total Mayo Score (TMS) at Week 12
The TMS was used to measure disease activity of ulcerative colitis. It consisted of 4 subscores \[stool frequency, rectal bleeding, findings of endoscopy (flexible proctosigmoidoscopy), and Physician's Global Assessment (PGA) score\], each of which was rated on a scale from 0 to 3, indicating normal to severe. The TMS was calculated as the sum of the 4 subscores, and the overall score values ranged from 0 to 12, with a higher score indicating more severe disease. Multiple imputation method was used to handle missing data.
Time frame: Baseline and Week 12
Population: The analysis was performed using the ITT population that consisted of all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Etrasimod 1 mg | Change From Baseline in Total Mayo Score (TMS) at Week 12 | -2.69 score on a scale |
| Etrasimod 2 mg | Change From Baseline in Total Mayo Score (TMS) at Week 12 | -3.35 score on a scale |
| Placebo | Change From Baseline in Total Mayo Score (TMS) at Week 12 | -2.08 score on a scale |
Comparison: The primary comparison in the study was between etrasimod 2 mg versus placebo.p-value: =0.0190% CI: [-2.17, -0.37]ANCOVA
p-value: =0.127790% CI: [-1.48, 0.27]ANCOVA
Secondary
Percentage of Participants Who Achieved Endoscopic Improvement at Week 12
For determination of the endoscopic subscore of the MCS, a flexible proctosigmoidoscopy, performed with a videoendoscope following a cleansing prep (oral or rectal cathartic) was performed at screening (within 10 days prior to administration of the first dose of study drug) and the Week 12 visit. This efficacy procedure assessed endoscopic mucosal appearance. The results were rated on a scale from 0 to 3, indicating normal to severe. Endoscopic improvement was defined as Mayo endoscopic subscore (using findings of flexible proctosigmoidoscopy) of ≤1 point. Multiple imputation method was used to handle missing data.
Time frame: Week 12
Population: The analysis was performed using the ITT population that consisted of all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etrasimod 1 mg | Percentage of Participants Who Achieved Endoscopic Improvement at Week 12 | 22.5 percentage of participants |
| Etrasimod 2 mg | Percentage of Participants Who Achieved Endoscopic Improvement at Week 12 | 41.8 percentage of participants |
| Placebo | Percentage of Participants Who Achieved Endoscopic Improvement at Week 12 | 17.8 percentage of participants |
Comparison: The primary comparison in the study was between etrasimod 2 mg versus placebo.p-value: =0.00390% CI: [9.8, 39]Mantel Haenszel
p-value: =0.305990% CI: [-9.1, 17.2]Mantel Haenszel
Other Pre-specified
Percentage of Participants Who Achieved Clinical Remission at Week 12
A participant was considered to have achieved clinical remission if he/she had: 1) an endoscopy score using flexible proctosigmoidoscopy of 0 or 1 (excluding friability), 2) a rectal bleeding score of 0 or 1, and 3) a stool frequency score of 0 or 1 with a decrease of ≥1 point from baseline. Multiple imputation method was used to handle missing data.
Time frame: Week 12
Population: The analysis was performed using the ITT population that consisted of all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etrasimod 1 mg | Percentage of Participants Who Achieved Clinical Remission at Week 12 | 16.0 percentage of participants |
| Etrasimod 2 mg | Percentage of Participants Who Achieved Clinical Remission at Week 12 | 33.0 percentage of participants |
| Placebo | Percentage of Participants Who Achieved Clinical Remission at Week 12 | 8.1 percentage of participants |
Comparison: The primary comparison in the study was between etrasimod 2 mg versus placebo.p-value: =0.000390% CI: [13.5, 38.1]Mantel Haenszel
p-value: =0.13690% CI: [-3.5, 17.7]Mantel Haenszel
Other Pre-specified
Percentage of Participants Who Achieved Clinical Response at Week 12
A participant was considered to have achieved clinical response if he/she met the criteria of clinical remission defined above, or met criteria of clinical response. Clinical response was defined as a decrease in the adapted MCS of ≥ 2 points and a decrease of ≥ 30% with either a decrease of rectal bleeding of ≥ 1 or rectal bleeding score of 0 or 1.
Time frame: Week 12
Population: The analysis was performed using the ITT population that consisted of all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Etrasimod 1 mg | Percentage of Participants Who Achieved Clinical Response at Week 12 | 43.7 percentage of participants |
| Etrasimod 2 mg | Percentage of Participants Who Achieved Clinical Response at Week 12 | 50.6 percentage of participants |
| Placebo | Percentage of Participants Who Achieved Clinical Response at Week 12 | 32.5 percentage of participants |
Comparison: The primary comparison in the study was between etrasimod 2 mg versus placebo.p-value: =0.028290% CI: [2.6, 35.3]Mantel Haenszel
p-value: =0.130990% CI: [-5.3, 28.1]Mantel Haenszel
Other Pre-specified
Trichotomous Composite Score of Clinical Remission and Clinical Response at Week 12
The trichotomous composite score of clinical remission and clinical response at Week 12 is an ordinal categorical endpoint with 3 categories (score ranging 0 to 2: score 2 for achieving both clinical remission and clinical response; 1 for only achieving clinical response, and 0 for achieving neither). Multiple imputation method was used to handle missing data.
Time frame: Week 12
Population: The analysis was performed using the ITT population that consisted of all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Etrasimod 1 mg | Trichotomous Composite Score of Clinical Remission and Clinical Response at Week 12 | 0.60 score on a scale | Standard Error 0.11 |
| Etrasimod 2 mg | Trichotomous Composite Score of Clinical Remission and Clinical Response at Week 12 | 0.84 score on a scale | Standard Error 0.13 |
| Placebo | Trichotomous Composite Score of Clinical Remission and Clinical Response at Week 12 | 0.41 score on a scale | Standard Error 0.09 |
Comparison: The primary comparison in the study was between etrasimod 2 mg versus placebo.p-value: =0.007190% CI: [1.4, 5.51]ANCOVA
p-value: =0.119290% CI: [0.83, 3.14]ANCOVA