Colitis, Ulcerative
Conditions
Keywords
T regulatory cells (Tregs), Interleukin 2, Interleukin-2
Brief summary
The reason for this study is to determine if the study drug LY3471851 is safe and effective in adult participants with active ulcerative colitis (UC). The study treatment will last about 52 weeks.
Detailed description
In stage 1, two doses (high and low) of LY3471851 will be compared to placebo. In stage 2, up to two additional doses (to be confirmed) of LY3471851 will be compared to placebo. LY3471851 (NKTR-358) is a potential first-in-class therapeutic that may address an underlying immune system imbalance in people with many autoimmune conditions. It targets the interleukin (IL-2) receptor complex in the body in order to stimulate proliferation of inhibitory immune cells known as regulatory T cells. By activating these cells, LY3471851 may act to bring the immune system back into balance.
Interventions
DRUGLY3471851
administered SC
DRUGPlacebo
administered SC
Sponsors
Eli Lilly and Company
Nektar Therapeutics
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
* Have moderately to severely active ulcerative colitis (UC) as defined by a modified Mayo score (MMS) of 4 to 9 with an endoscopic subscore (ES) ≥2, with endoscopy performed within 14 days before baseline. * Have evidence of UC extending proximal to the rectum (with ≥15 centimeters (cm) of involved colon). * Have up-to-date colorectal cancer surveillance performed according to local standard. * Participants are either one of the following: * Have failed conventional treatments including inability to tolerate oral or intravenous corticosteroids or immunomodulators (6-mercaptopurine or azathioprine or methotrexate), or history of corticosteroid dependence (an inability to successfully taper corticosteroids without return of UC) and neither failed or demonstrated intolerance to advanced therapy (eg, tumor necrosis factor (TNF) antagonists, anti-integrin therapies, anti-IL12/23p40 therapies, Janus kinase (JAK) inhibitor) OR, * Have failed advanced therapies such as treatment with 1 or more advance therapies (eg, tumor necrosis factor \[TNF\] antagonists, anti-integrin therapies, anti-IL12/23p40 therapies, Janus kinase \[JAK\] inhibitor) at doses approved for the treatment of UC with documented history of failure to respond to or tolerate such treatment. * Have had an established diagnosis of UC of ≥3 months in duration before baseline which includes endoscopic evidence of UC and a histopathology report that supports a diagnosis of UC. Supportive endoscopy and histopathology reports must be available in the source documents. * Women of child-bearing potential (WOCBP) must test negative for pregnancy as indicated by a negative serum pregnancy test at the screening visit followed by a negative urine pregnancy test within 24 hours prior to first exposure to study drug.
Exclusion criteria
* Have been diagnosed with indeterminant colitis, proctitis (colitis limited to the rectum only; less than 15 centimeter (cm) from the anal verge or Crohn's disease. * Have received any of the following for treatment of UC: cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide within 2 weeks of screening, rectally administered corticosteroids or 5-aminosalicylic acid treatments within 2 weeks of screening. * Have had or will need abdominal surgery for UC (for example, subtotal colectomy). * Have failed 3 or more classes of advanced therapies approved for treatment of UC (eg, tumor necrosis factor \[TNF\] antagonists, anti-integrin therapies, anti-IL12/23p40 therapies, Janus kinase \[JAK\] inhibitor). * Have evidence of toxic megacolon, intra-abdominal abscess, or stricture/stenosis within the small bowel or colon. * Have any history or evidence of cancer of the gastrointestinal tract * Have myocardial infarction, unstable ischemic heart disease, stroke or heart failure within 12 months prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Clinical Remission at Week 12 | Week 12 | Clinical remission is defined as achieving a Modified Mayo Score (MMS) sub-score for rectal bleeding=0, stool frequency=0, or stool frequency=1 with ≥ 1 point decrease from baseline, and endoscopy=0 or 1 (excluding friability). The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Endoscopic Remission at Week 12 | Week 12 | Endoscopic remission is defined as achieving a MMS sub-score for endoscopy=0 or 1 (excluding friability). The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity. |
| Percentage of Participants Who Achieved Endoscopic Response at Week 12 | Week 12 | Endoscopic response is defined as a decrease of ≥1 point in the MMS endoscopy sub-score from baseline. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity. |
| Percentage of Participants Who Achieved Symptomatic Remission at Week 12 | Week 12 | Symptomatic remission is defined as achieving a MMS sub-score for stool frequency=0, or stool frequency=1 with a decrease of ≥1 point from baseline, and rectal bleeding =0. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity. |
| Percentage of Participants Who Achieved Symptomatic Response at Week 12 | Week 12 | Symptomatic response is defined as a ≥30% decrease from baseline in the composite clinical endpoint of the sum of MMS sub-scores of stool frequency and rectal bleeding. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity. |
| Percentage of Participants Who Achieved Clinical Response at Week 12 | Week 12 | Clinical response is defined as a decrease in the MMS of ≥2 points and ≥30% decrease from baseline, and a decrease of ≥1 point in the rectal bleeding sub-score from baseline or a rectal bleeding score of 0 or 1. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity. |
| Percentage of Participants Who Achieved Histologic-Endoscopic Mucosal Healing (HEMH) | Week 12 | HEMH is defined as Geboes score \<2 AND endoscopic remission. Geboes score is a 7-item instrument used to identify histologic changes in UC. The 7-items are Grade 0: Architectural changes (0=No abnormality to 3=Severe diffuse or multifocal abnormalities); Grade 1: Chronic inflammatory infiltrate (0=No increase to 3=Marked increase); Grade 2A: lamina propria eosinophils (0=No increase to 3=Marked increase); Grade 2B: lamina propria neutrophils (0= No increase to 3=Marked increase); Grade 3: Neutrophils in epithelium (0=None to 3=\>50% crypts involved); Grade 4: Crypt destruction(0=none to 3=Unequivocal crypt destruction),and Grade 5: Erosion or ulceration:(0=No erosion, ulceration or granulation to 4=Ulcer or granulation tissue). The grade with severe histological observation is considered the Geboes score and ranges from 0 to 4, with higher scores indicating severe disease. Endoscopic remission is defined as achieving a MMS sub-score for endoscopy=0 or 1 (excluding friability). |
| Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) - Total Score | Baseline, Week 12 | IBDQ is a 32-item questionnaire that measures four aspects of participants' lives: symptoms directly related to the primary bowel disturbance (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items). Responses are graded on a 7-point Likert scale, where 7 denotes not a problem at all and 1 denotes a very severe problem. The responses are summed to produce a total score ranging from 32 to 224, with higher score indicating a better quality of life. LS Mean was calculated using ANCOVA (analysis of covariance) model with treatment, baseline value, previous advanced therapy failure status (yes/no), baseline corticosteroid use (yes/no), baseline disease activity (MMS: \[4 to 6\] or \[7 to 9\]) and region (North America/Europe/Other) as fixed factors. |
| Pharmacokinetics (PK): Trough Concentration of LY3471851 (Ctrough) at Week 12 | Predose at week 12 | C-trough is the concentration of drug in the blood immediately before the next dose was administered. |
| Percentage of Participants Who Achieved Histologic Remission at Week 12 | Week 12 | Histologic Remission is defined as Geboes score \<2 or subscores = 0 for Grade 2a, 2b, 3, 4, and 5. The Geboes score is a 7-item instrument used to identify histologic changes in UC. The 7 items are Grade 0: Architectural changes (0=No abnormality to 3=Severe diffuse or multifocal abnormalities); Grade 1: Chronic inflammatory infiltrate (0=No increase to 3=Marked increase); Grade 2A: lamina propria eosinophils (0=No increase to 3=Marked increase); Grade 2B: lamina propria neutrophils (0= No increase to 3=Marked increase); Grade 3: Neutrophils in epithelium (0=None to 3=\>50% crypts involved); Grade 4: Crypt destruction(0=none to 3=Unequivocal crypt destruction),and Grade 5: Erosion or ulceration:(0=No erosion, ulceration or granulation to 4=Ulcer or granulation tissue). The grade with severe histological observation is considered the Geboes score and ranges from 0 to 4, with higher scores indicating severe disease. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, Czechia, France, Georgia, Hungary, India, Israel, Japan, Latvia, Poland, Romania, Russia, Slovakia, South Korea, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study consisted of: * a 12-week induction treatment period: participants randomly received either high dose LY3471851 or low dose LY3471851 or placebo. * a 40-week maintenance/extension treatment period (final dose at week 50 and study assessments at week 52) * (i) Week 12 responders enter the maintenance period where they continued to receive the same treatment to which they were randomly assigned. (Continued..)
Pre-assignment details
* (ii) Week 12 non-responders enter the extension period where they received high dose LY3471851. At week 26, those who responded to treatment continued with the same treatment, while non-responders discontinued and entered follow-up. * a 6-week post-treatment follow-up period: Following treatment completion or discontinuation, participants entered the follow-up period and were observed for safety. No treatments were administered.
Participants by arm
| Arm | Count |
|---|---|
| High Dose LY3471851 (Induction Treatment Period) Participants received a subcutaneous injection of high dose LY3471851 every 2 weeks from weeks 0 to 12. | 32 |
| Low Dose LY3471851 (Induction Treatment Period) Participants received a subcutaneous injection of low dose LY3471851 every 2 weeks from weeks 0 to 12. | 35 |
| Placebo (Induction Treatment Period) Participants received a subcutaneous injection of placebo every 2 weeks from weeks 0 to 12. | 14 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Extension Treatment Period | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 0 | 6 | 0 | 0 | 0 |
| Extension Treatment Period | Study terminated by sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 18 | 0 | 0 | 0 |
| Extension Treatment Period | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 |
| Induction Treatment Period | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction Treatment Period | Physician Decision | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction Treatment Period | Protocol Violation | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction Treatment Period | Study terminated by sponsor | 7 | 11 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction Treatment Period | Withdrawal by Subject | 4 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Maintenance Treatment Period | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Maintenance Treatment Period | Study terminated by sponsor | 0 | 0 | 0 | 7 | 9 | 5 | 0 | 0 | 0 | 0 |
| Maintenance Treatment Period | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Post-Treatment Follow-up Period | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Post-Treatment Follow-up Period | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 3 | 0 |
| Post-Treatment Follow-up Period | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Post-Treatment Follow-up Period | Study terminated by sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 18 | 26 | 11 |
| Post-Treatment Follow-up Period | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | High Dose LY3471851 (Induction Treatment Period) | Low Dose LY3471851 (Induction Treatment Period) | Placebo (Induction Treatment Period) |
|---|---|---|---|---|
| Age, Continuous | 42.6 years STANDARD_DEVIATION 13.7 | 39.2 years STANDARD_DEVIATION 12.5 | 44.5 years STANDARD_DEVIATION 13.8 | 45.7 years STANDARD_DEVIATION 15.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 5 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants | 0 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 | 68 Participants | 25 Participants | 31 Participants | 12 Participants |
| Region of Enrollment Argentina | 4 Participants | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Australia | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Belgium | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Czechia | 6 Participants | 2 Participants | 4 Participants | 0 Participants |
| Region of Enrollment Hungary | 6 Participants | 3 Participants | 3 Participants | 0 Participants |
| Region of Enrollment Japan | 5 Participants | 3 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Latvia | 5 Participants | 2 Participants | 3 Participants | 0 Participants |
| Region of Enrollment Poland | 5 Participants | 2 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Russia | 13 Participants | 5 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Slovakia | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Region of Enrollment South Korea | 5 Participants | 1 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Ukraine | 18 Participants | 7 Participants | 7 Participants | 4 Participants |
| Region of Enrollment United States | 8 Participants | 3 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Female | 25 Participants | 10 Participants | 9 Participants | 6 Participants |
| Sex: Female, Male Male | 56 Participants | 22 Participants | 26 Participants | 8 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 35 | 0 / 14 | 0 / 8 | 0 / 10 | 0 / 5 | 0 / 26 | 0 / 25 | 0 / 30 | 0 / 11 |
| other Total, other adverse events | 20 / 32 | 15 / 35 | 5 / 14 | 4 / 8 | 6 / 10 | 1 / 5 | 5 / 26 | 0 / 25 | 1 / 30 | 1 / 11 |
| serious Total, serious adverse events | 2 / 32 | 0 / 35 | 0 / 14 | 0 / 8 | 1 / 10 | 0 / 5 | 0 / 26 | 0 / 25 | 1 / 30 | 0 / 11 |
Outcome results
Primary
Percentage of Participants Who Achieved Clinical Remission at Week 12
Clinical remission is defined as achieving a Modified Mayo Score (MMS) sub-score for rectal bleeding=0, stool frequency=0, or stool frequency=1 with ≥ 1 point decrease from baseline, and endoscopy=0 or 1 (excluding friability). The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug and had MMS data at week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Induction Treatment Period) | Percentage of Participants Who Achieved Clinical Remission at Week 12 | 14.3 percentage of participants |
| Low Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Clinical Remission at Week 12 | 7.1 percentage of participants |
| High Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Clinical Remission at Week 12 | 17.2 percentage of participants |
p-value: 0.7595% CI: [0.03, 11.32]Cochran-Mantel-Haenszel
p-value: 0.83895% CI: [0.1, 6.21]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) - Total Score
IBDQ is a 32-item questionnaire that measures four aspects of participants' lives: symptoms directly related to the primary bowel disturbance (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items). Responses are graded on a 7-point Likert scale, where 7 denotes not a problem at all and 1 denotes a very severe problem. The responses are summed to produce a total score ranging from 32 to 224, with higher score indicating a better quality of life. LS Mean was calculated using ANCOVA (analysis of covariance) model with treatment, baseline value, previous advanced therapy failure status (yes/no), baseline corticosteroid use (yes/no), baseline disease activity (MMS: \[4 to 6\] or \[7 to 9\]) and region (North America/Europe/Other) as fixed factors.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of study drug and had IBDQ data at baseline, week 12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Induction Treatment Period) | Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) - Total Score | 26.71 score on a scale | Standard Error 9.346 |
| Low Dose LY3471851 (Induction Treatment Period) | Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) - Total Score | 36.42 score on a scale | Standard Error 7.64 |
| High Dose LY3471851 (Induction Treatment Period) | Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) - Total Score | 25.76 score on a scale | Standard Error 7.143 |
p-value: 0.37895% CI: [-12.17, 31.6]ANCOVA
p-value: 0.92895% CI: [-21.78, 19.88]ANCOVA
Secondary
Percentage of Participants Who Achieved Clinical Response at Week 12
Clinical response is defined as a decrease in the MMS of ≥2 points and ≥30% decrease from baseline, and a decrease of ≥1 point in the rectal bleeding sub-score from baseline or a rectal bleeding score of 0 or 1. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug and had MMS data at week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Induction Treatment Period) | Percentage of Participants Who Achieved Clinical Response at Week 12 | 35.7 percentage of participants |
| Low Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Clinical Response at Week 12 | 39.3 percentage of participants |
| High Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Clinical Response at Week 12 | 41.4 percentage of participants |
p-value: 0.56395% CI: [0.1, 3.3]Cochran-Mantel-Haenszel
p-value: 0.75995% CI: [0.17, 3.64]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieved Endoscopic Remission at Week 12
Endoscopic remission is defined as achieving a MMS sub-score for endoscopy=0 or 1 (excluding friability). The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug and had MMS data at week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Induction Treatment Period) | Percentage of Participants Who Achieved Endoscopic Remission at Week 12 | 28.6 percentage of participants |
| Low Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Endoscopic Remission at Week 12 | 14.3 percentage of participants |
| High Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Endoscopic Remission at Week 12 | 24.1 percentage of participants |
p-value: 0.16395% CI: [0.02, 1.93]Cochran-Mantel-Haenszel
p-value: 0.43995% CI: [0.11, 2.77]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieved Endoscopic Response at Week 12
Endoscopic response is defined as a decrease of ≥1 point in the MMS endoscopy sub-score from baseline. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug and had MMS data at week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Induction Treatment Period) | Percentage of Participants Who Achieved Endoscopic Response at Week 12 | 21.4 percentage of participants |
| Low Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Endoscopic Response at Week 12 | 32.1 percentage of participants |
| High Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Endoscopic Response at Week 12 | 37.9 percentage of participants |
p-value: 0.82195% CI: [0.17, 9.88]Cochran-Mantel-Haenszel
p-value: 0.57295% CI: [0.37, 5.49]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieved Histologic-Endoscopic Mucosal Healing (HEMH)
HEMH is defined as Geboes score \<2 AND endoscopic remission. Geboes score is a 7-item instrument used to identify histologic changes in UC. The 7-items are Grade 0: Architectural changes (0=No abnormality to 3=Severe diffuse or multifocal abnormalities); Grade 1: Chronic inflammatory infiltrate (0=No increase to 3=Marked increase); Grade 2A: lamina propria eosinophils (0=No increase to 3=Marked increase); Grade 2B: lamina propria neutrophils (0= No increase to 3=Marked increase); Grade 3: Neutrophils in epithelium (0=None to 3=\>50% crypts involved); Grade 4: Crypt destruction(0=none to 3=Unequivocal crypt destruction),and Grade 5: Erosion or ulceration:(0=No erosion, ulceration or granulation to 4=Ulcer or granulation tissue). The grade with severe histological observation is considered the Geboes score and ranges from 0 to 4, with higher scores indicating severe disease. Endoscopic remission is defined as achieving a MMS sub-score for endoscopy=0 or 1 (excluding friability).
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug and had Geboes, MMS data at week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Induction Treatment Period) | Percentage of Participants Who Achieved Histologic-Endoscopic Mucosal Healing (HEMH) | 0 percentage of participants |
| Low Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Histologic-Endoscopic Mucosal Healing (HEMH) | 3.6 percentage of participants |
| High Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Histologic-Endoscopic Mucosal Healing (HEMH) | 6.9 percentage of participants |
p-value: 0.31795% CI: [-3.3, 10.4]Cochran-Mantel-Haenszel
p-value: 0.23895% CI: [-2.3, 16.1]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieved Histologic Remission at Week 12
Histologic Remission is defined as Geboes score \<2 or subscores = 0 for Grade 2a, 2b, 3, 4, and 5. The Geboes score is a 7-item instrument used to identify histologic changes in UC. The 7 items are Grade 0: Architectural changes (0=No abnormality to 3=Severe diffuse or multifocal abnormalities); Grade 1: Chronic inflammatory infiltrate (0=No increase to 3=Marked increase); Grade 2A: lamina propria eosinophils (0=No increase to 3=Marked increase); Grade 2B: lamina propria neutrophils (0= No increase to 3=Marked increase); Grade 3: Neutrophils in epithelium (0=None to 3=\>50% crypts involved); Grade 4: Crypt destruction(0=none to 3=Unequivocal crypt destruction),and Grade 5: Erosion or ulceration:(0=No erosion, ulceration or granulation to 4=Ulcer or granulation tissue). The grade with severe histological observation is considered the Geboes score and ranges from 0 to 4, with higher scores indicating severe disease.
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug and had Geboes data at week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Induction Treatment Period) | Percentage of Participants Who Achieved Histologic Remission at Week 12 | 7.1 percentage of participants |
| Low Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Histologic Remission at Week 12 | 7.1 percentage of participants |
| High Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Histologic Remission at Week 12 | 10.3 percentage of participants |
p-value: 0.56495% CI: [0.38, 6]Cochran-Mantel-Haenszel
p-value: 0.68195% CI: [0.21, 10.97]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieved Symptomatic Remission at Week 12
Symptomatic remission is defined as achieving a MMS sub-score for stool frequency=0, or stool frequency=1 with a decrease of ≥1 point from baseline, and rectal bleeding =0. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug and had MMS data at week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Induction Treatment Period) | Percentage of Participants Who Achieved Symptomatic Remission at Week 12 | 21.4 percentage of participants |
| Low Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Symptomatic Remission at Week 12 | 32.1 percentage of participants |
| High Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Symptomatic Remission at Week 12 | 27.6 percentage of participants |
p-value: 0.88695% CI: [0.14, 10.16]Cochran-Mantel-Haenszel
p-value: 0.78495% CI: [0.14, 4.18]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieved Symptomatic Response at Week 12
Symptomatic response is defined as a ≥30% decrease from baseline in the composite clinical endpoint of the sum of MMS sub-scores of stool frequency and rectal bleeding. The MMS is a scoring system for assessment of UC and is composed of sub-scores of stool frequency (range: 0 to 3, where 0=normal number of stools, 3=5 or more stools more than normal), endoscopy (range: 0 to 3, where 0=normal or inactive disease, 3=severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0=no blood seen, 3=blood alone passed). Total MMS score is sum of all sub-scores and ranges from 0 to 9, with higher scores indicating higher disease activity.
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug and had MMS data at week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Induction Treatment Period) | Percentage of Participants Who Achieved Symptomatic Response at Week 12 | 42.9 percentage of participants |
| Low Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Symptomatic Response at Week 12 | 42.9 percentage of participants |
| High Dose LY3471851 (Induction Treatment Period) | Percentage of Participants Who Achieved Symptomatic Response at Week 12 | 44.8 percentage of participants |
p-value: 0.33195% CI: [0.06, 2.43]Cochran-Mantel-Haenszel
p-value: 0.40795% CI: [0.1, 2.52]Cochran-Mantel-Haenszel
Secondary
Pharmacokinetics (PK): Trough Concentration of LY3471851 (Ctrough) at Week 12
C-trough is the concentration of drug in the blood immediately before the next dose was administered.
Time frame: Predose at week 12
Population: All participants who received at least 1 dose of LY3471851 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Induction Treatment Period) | Pharmacokinetics (PK): Trough Concentration of LY3471851 (Ctrough) at Week 12 | 91.3 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 49 |
| Low Dose LY3471851 (Induction Treatment Period) | Pharmacokinetics (PK): Trough Concentration of LY3471851 (Ctrough) at Week 12 | 139 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 105 |