Colitis, Ulcerative
Conditions
Brief summary
The purpose of the study is to evaluate the efficacy and safety of LYC-30937-EC given orally once daily in subjects with active ulcerative colitis (UC) defined as a total Mayo score (TMS) of 4-11 inclusive, with an endoscopic score of ≥ 2 and a rectal bleeding score of ≥ 1 at screening.
Detailed description
Approximately 120 subjects will be randomized to receive either enteric-coated (EC) LYC-30937-EC 25 mg PO once daily (QD) or matching placebo PO QD for the duration of 8 weeks. Randomization will be stratified based on previous exposure to anti-tumor necrosis factor (TNF) agents such that at least 50% of the randomized subjects will be anti-TNF naïve . The study will consist of 3 phases: * screening phase: up to 4 weeks * double-blind placebo-controlled phase treatment: 8 weeks * post-treatment follow-up: 2 weeks Eligible subjects will be randomized at Week 0 (Study Day 1) to either LYC-30937-EC 25 mg or placebo. Screening will occur from Study Days -28 to -1. Randomization and first dosing will occur at Week 0/Study Day 1. Double-blind study visits will occur at Weeks 2, 4, and 8, with the last dose at Week 8/Study Day 57. Subjects will return at Week 10 for a post-treatment safety follow-up visit.
Interventions
DRUGLYC-30937-EC
DRUGPlacebo
Sponsors
Lycera Corp.
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
* Clinical UC diagnosis ≥ 6 months prior to screening with minimum disease extent of ≥ 15cm from anal verge. * Active UC defined as a TMS of 4-11 (inclusive) with endoscopic subscore of ≥ 2 and rectal bleeding subscore of ≥ 1 at screening. * Females of childbearing potential must have a negative pregnancy test at screening and baseline visits and must agree to use acceptable methods of birth control while in the trial and for 30 days after taking the last dose of study drug. * May be currently receiving treatment with oral aminosalicylates (ASA) for ≥ 6 weeks at a stable dose for ≥ 3 weeks prior to the screening screening endoscopy and/or thiopurine at a stable dose ≥ 8 weeks prior to the screening endoscopy and/or prednisone (dose 20 mg daily) or equivalent for ≥ 4 weeks and receiving stable dose for ≥ 2 weeks prior to screening endoscopy * able to provide written informed consent and be compliant with study procedures.
Exclusion criteria
* History of Crohn's disease (CD) or indeterminate colitis or the presence or history of fistula consistent with CD. * Presence of colon polyps. * Severe extensive disease that in the investigators discretion is likely to require colonic surgery during the 8 week double-blind portion of the trial (eg, fulminant colitis, toxic megacolon, bowel perforation, evidence of acute abdomen). * History of alcohol or drug abuse within 1 year of randomization. * History of cancer including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been adequately treated with no recurrence for ≥ 1 year prior to screening. * History or currently active primary or secondary immunodeficiency. * Clinically relevant hepatic, neurologic, pulmonary, ophthalmological, gastrointestinal, endocrine, psychiatric, or other major systemic disease making implementation of the study difficult or that would put the subject at risk by participating in the study * Positive test for Clostridium difficile or positive stool culture for enteric pathogens or presence of ova or parasites at screening. * Liver function tests \> 1.5 x upper limit of normal (ULN) or direct bilirubin \> 1.5 x ULN * Hemoglobin \< 8.5 g/dl * Neutrophils \< 1500/mm3 * White blood cell (WBC) count \< 3000/mm3 * Platelets \< 80000 mm3 * International normalized ratio (INR) \> 1.5 * Treatment with an immunosuppressant agent within 8 weeks of screening. * Previous exposure to ≥ 2 approved or investigational biologic agents to treat UC. * History of UC treatment with a biologic agent within 12 weeks of screening. * Treatment with rectal steroids within 2 weeks of screening. * Treatment with an investigational agent within 30 days of screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Achieve Clinical Remission at Week 8 Using Modified Mayo Score. | 8 weeks | The modified Mayo score is a tool designed to measure disease activity for ulcerative colitis. Scoring ranges from 0 to 9 points and consists of 3 subscores (stool frequency, rectal bleeding, endoscopy), each graded 0 to 3 with higher score indicating more severe disease activity. Endoscopy scoring was performed centrally. Clinical remission on the modified Mayo score was defined as a Mayo stool frequency subscore of ≤ 1, Mayo rectal bleeding subscore of 0 and a Mayo endoscopy subscore of ≤ 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Achieve Clinical Remission at Week 8 Using the Total Mayo Score. | 8 weeks | The total Mayo score is a tool designed to measure disease activity for ulcerative colitis. Scoring ranges from 0 to 12 points and consists of 4 subscores (stool frequency, rectal bleeding, endoscopy, physicians global assessment), each graded 0 to 3 with higher score indicating more severe disease activity. Endoscopy scoring was performed centrally. Clinical remission on the total Mayo Score is defined as a total Mayo score of ≤ 2, with no individual subscore \> 1. |
| Number of Subjects With a Clinical Response on the Modified Mayo Score at Week 8. | 8 weeks | The modified Mayo score is a tool designed to measure disease activity for ulcerative colitis. Scoring ranges from 0 to 9 points and consists of 3 subscores (stool frequency, rectal bleeding, endoscopy), each graded 0 to 3 with higher score indicating more severe disease activity. Endoscopy scoring was performed centrally. Clinical response on the modified Mayo score at Week 8 was defined as a reduction from the baseline modified Mayo score of ≥ 2 points and ≥ 25%, and a decrease from baseline in rectal bleeding score of ≥ 1 point or absolute rectal bleeding score of ≤ 1 point. |
| Percent Change From Baseline to Week 8 in Fecal Calprotectin in Subjects With Baseline Fecal Calprotectin ≥ 250 µg/g | Baseline to Week 8 | Fecal calprotectin is an indicator of inflammation in the colon with higher levels indicative of higher levels of inflammation. |
| Percent Change From Baseline in Total Mayo Score at Week 8. | Baseline to Week 8 | Analyzes the change in total Mayo score score between baseline and Week 8 for all randomized subjects who had total Mayo score scores at both baseline and Week 8. The total Mayo score is a tool designed to measure disease activity for ulcerative colitis. Scoring ranges from 0 to 12 points and consists of 4 subscores (stool frequency, rectal bleeding, endoscopy, physicians global assessment), each graded 0 to 3 with higher score indicating more severe disease activity. Endoscopy scoring was performed centrally. |
| Number of Subjects With a Clinical Response on the Total Mayo Score at Week 8. | 8 weeks | The total Mayo score is a tool designed to measure disease activity for ulcerative colitis. Scoring ranges from 0 to 12 points and consists of 4 subscores (stool frequency, rectal bleeding, endoscopy, physicians global assessment), each graded 0 to 3 with higher score indicating more severe disease activity. Endoscopy scoring was performed centrally. Clinical response on the total Mayo score at Week 8 was defined as a reduction from baseline total Mayo score of ≥ 3 points and ≥ 30%, and a decrease from baseline in rectal bleeding score of ≥ 1 point or absolute rectal bleeding score of ≤ 1 point. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Type of Adverse Events (AEs) Serious Adverse Events (SAEs) and AEs That Led to Discontinuation of Treatment. | 10 weeks | Adverse events (AEs) were collected from the time a subject signed the informed consent. Treatment-emergent adverse events (TEAEs) are AEs occurring or worsening after the first dose of study drug (LYC-30937-EC 25 mg or placebo). Adverse event severity was assessed by the Investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.03, with grading as follows: Grade 1 = mild (asymptomatic or mild symptoms), Grade 2 = moderate (minimal, local intervention, or noninvasive intervention indicated); Grade 3 = severe (or medically significant but not life-threatening); Grade 4 = life-threatening; Grade 5 = death. |
Countries
Canada, Czechia, Hungary, Netherlands, Poland, Serbia, United States
Participant flow
Recruitment details
Participants were enrolled at 42 study centers within the United States, Poland, Hungary, Czech Republic, Serbia and Netherlands. Study centers included academic medical centers and non-academic medical clinics.
Pre-assignment details
Participants were 18 to 75 years of age with active ulcerative colitis for at least 6 months prior to screening, had a total Mayo score (TMS) ≥ 4 to ≤ 11, with endoscopic subscore ≥ 2, and rectal bleeding subscore ≥ 1 at screening.
Participants by arm
| Arm | Count |
|---|---|
| LYC-30937-EC LYC-30937-EC 25 mg by mouth once daily for 8 weeks | 62 |
| Placebo Matching placebo by mouth once daily for 8 weeks | 62 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | LYC-30937-EC | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 43.8 years STANDARD_DEVIATION 11.94 | 39.3 years STANDARD_DEVIATION 13.26 | 41.5 years STANDARD_DEVIATION 12.77 |
| Baseline Total Mayo Score (TMS) and Modified Mayo Score (MMS) Baseline MMS Mean (Standard Deviation) | 6.0 units on a scale STANDARD_DEVIATION 1.38 | 5.7 units on a scale STANDARD_DEVIATION 1.55 | 5.8 units on a scale STANDARD_DEVIATION 1.47 |
| Baseline Total Mayo Score (TMS) and Modified Mayo Score (MMS) Baseline TMS Mean (Standard Deviation) | 7.9 units on a scale STANDARD_DEVIATION 1.46 | 7.8 units on a scale STANDARD_DEVIATION 1.77 | 7.9 units on a scale STANDARD_DEVIATION 1.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants | 58 Participants | 117 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 60 Participants | 59 Participants | 119 Participants |
| Region of Enrollment Czechia | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Hungary | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Netherlands | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Poland | 43 participants | 38 participants | 81 participants |
| Region of Enrollment Serbia | 2 participants | 3 participants | 5 participants |
| Region of Enrollment United States | 11 participants | 17 participants | 28 participants |
| Sex: Female, Male Female | 27 Participants | 25 Participants | 52 Participants |
| Sex: Female, Male Male | 35 Participants | 37 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 62 | 0 / 62 |
| other Total, other adverse events | 10 / 62 | 11 / 62 |
| serious Total, serious adverse events | 1 / 62 | 3 / 62 |
Outcome results
Primary
Number of Subjects Who Achieve Clinical Remission at Week 8 Using Modified Mayo Score.
The modified Mayo score is a tool designed to measure disease activity for ulcerative colitis. Scoring ranges from 0 to 9 points and consists of 3 subscores (stool frequency, rectal bleeding, endoscopy), each graded 0 to 3 with higher score indicating more severe disease activity. Endoscopy scoring was performed centrally. Clinical remission on the modified Mayo score was defined as a Mayo stool frequency subscore of ≤ 1, Mayo rectal bleeding subscore of 0 and a Mayo endoscopy subscore of ≤ 1.
Time frame: 8 weeks
Population: The analysis population consisted of all randomized subjects (Full Analysis Set).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LYC-30937-EC 25 mg PO QD | Number of Subjects Who Achieve Clinical Remission at Week 8 Using Modified Mayo Score. | 7 Participants |
| Placebo PO QD | Number of Subjects Who Achieve Clinical Remission at Week 8 Using Modified Mayo Score. | 12 Participants |
Comparison: The response rate difference is the mean difference in response rates between the treatment and placebo responders. The p-value is based on one-sided Pearson chi-square test.p-value: 0.10690% CI: [-18.6, 2.5]Chi-squared
Secondary
Number of Subjects Who Achieve Clinical Remission at Week 8 Using the Total Mayo Score.
The total Mayo score is a tool designed to measure disease activity for ulcerative colitis. Scoring ranges from 0 to 12 points and consists of 4 subscores (stool frequency, rectal bleeding, endoscopy, physicians global assessment), each graded 0 to 3 with higher score indicating more severe disease activity. Endoscopy scoring was performed centrally. Clinical remission on the total Mayo Score is defined as a total Mayo score of ≤ 2, with no individual subscore \> 1.
Time frame: 8 weeks
Population: The analysis population consisted of all randomized subjects (Full Analysis Set).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LYC-30937-EC 25 mg PO QD | Number of Subjects Who Achieve Clinical Remission at Week 8 Using the Total Mayo Score. | 7 Participants |
| Placebo PO QD | Number of Subjects Who Achieve Clinical Remission at Week 8 Using the Total Mayo Score. | 12 Participants |
Comparison: The response rate difference is the mean difference in response rates between the treatment and placebo responders. The p-value is based on one-sided Pearson chi-square test.p-value: 0.10690% CI: [-18.6, 2.5]Chi-squared
Secondary
Number of Subjects With a Clinical Response on the Modified Mayo Score at Week 8.
The modified Mayo score is a tool designed to measure disease activity for ulcerative colitis. Scoring ranges from 0 to 9 points and consists of 3 subscores (stool frequency, rectal bleeding, endoscopy), each graded 0 to 3 with higher score indicating more severe disease activity. Endoscopy scoring was performed centrally. Clinical response on the modified Mayo score at Week 8 was defined as a reduction from the baseline modified Mayo score of ≥ 2 points and ≥ 25%, and a decrease from baseline in rectal bleeding score of ≥ 1 point or absolute rectal bleeding score of ≤ 1 point.
Time frame: 8 weeks
Population: The analysis population consisted of all randomized subjects (Full Analysis Set).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LYC-30937-EC 25 mg PO QD | Number of Subjects With a Clinical Response on the Modified Mayo Score at Week 8. | 32 Participants |
| Placebo PO QD | Number of Subjects With a Clinical Response on the Modified Mayo Score at Week 8. | 36 Participants |
Comparison: The response rate difference is the mean difference in response rates between the treatment and placebo responders. The p-value is based on one-sided Pearson chi-square test.p-value: 0.23590% CI: [-21.1, 8.2]Chi-squared
Secondary
Number of Subjects With a Clinical Response on the Total Mayo Score at Week 8.
The total Mayo score is a tool designed to measure disease activity for ulcerative colitis. Scoring ranges from 0 to 12 points and consists of 4 subscores (stool frequency, rectal bleeding, endoscopy, physicians global assessment), each graded 0 to 3 with higher score indicating more severe disease activity. Endoscopy scoring was performed centrally. Clinical response on the total Mayo score at Week 8 was defined as a reduction from baseline total Mayo score of ≥ 3 points and ≥ 30%, and a decrease from baseline in rectal bleeding score of ≥ 1 point or absolute rectal bleeding score of ≤ 1 point.
Time frame: 8 weeks
Population: The analysis population consisted of all randomized subjects (Full Analysis Set).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LYC-30937-EC 25 mg PO QD | Number of Subjects With a Clinical Response on the Total Mayo Score at Week 8. | 26 Participants |
| Placebo PO QD | Number of Subjects With a Clinical Response on the Total Mayo Score at Week 8. | 32 Participants |
Comparison: The response rate difference is the mean difference in response rates between the treatment and placebo responders. The p-value is based on one-sided Pearson chi-square test.p-value: 0.1490% CI: [-24.3, 5]Chi-squared
Secondary
Percent Change From Baseline in Total Mayo Score at Week 8.
Analyzes the change in total Mayo score score between baseline and Week 8 for all randomized subjects who had total Mayo score scores at both baseline and Week 8. The total Mayo score is a tool designed to measure disease activity for ulcerative colitis. Scoring ranges from 0 to 12 points and consists of 4 subscores (stool frequency, rectal bleeding, endoscopy, physicians global assessment), each graded 0 to 3 with higher score indicating more severe disease activity. Endoscopy scoring was performed centrally.
Time frame: Baseline to Week 8
Population: All randomized subjects randomized who had TMS scores at baseline and Week 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LYC-30937-EC 25 mg PO QD | Percent Change From Baseline in Total Mayo Score at Week 8. | -2.49 Percent Change from baseline | Standard Error 0.33 |
| Placebo PO QD | Percent Change From Baseline in Total Mayo Score at Week 8. | -2.67 Percent Change from baseline | Standard Error 0.33 |
p-value: 0.70890% CI: [-0.6, 0.95]ANCOVA
Secondary
Percent Change From Baseline to Week 8 in Fecal Calprotectin in Subjects With Baseline Fecal Calprotectin ≥ 250 µg/g
Fecal calprotectin is an indicator of inflammation in the colon with higher levels indicative of higher levels of inflammation.
Time frame: Baseline to Week 8
Population: All randomized subjects who had an elevated baseline fecal calprotectin level of ≥ 250 µg/g and who had both a baseline and Week 8 value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LYC-30937-EC 25 mg PO QD | Percent Change From Baseline to Week 8 in Fecal Calprotectin in Subjects With Baseline Fecal Calprotectin ≥ 250 µg/g | -35.22 percent change from baseline | Standard Error 13.81 |
| Placebo PO QD | Percent Change From Baseline to Week 8 in Fecal Calprotectin in Subjects With Baseline Fecal Calprotectin ≥ 250 µg/g | 9.37 percent change from baseline | Standard Error 15.07 |
Comparison: Subjects included in this analysis were those with a baseline fecal calprotectin value ≥ 250 µg/g.p-value: 0.03290% CI: [-78.66, -10.53]ANCOVA
Other Pre-specified
Number of Subjects With Type of Adverse Events (AEs) Serious Adverse Events (SAEs) and AEs That Led to Discontinuation of Treatment.
Adverse events (AEs) were collected from the time a subject signed the informed consent. Treatment-emergent adverse events (TEAEs) are AEs occurring or worsening after the first dose of study drug (LYC-30937-EC 25 mg or placebo). Adverse event severity was assessed by the Investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.03, with grading as follows: Grade 1 = mild (asymptomatic or mild symptoms), Grade 2 = moderate (minimal, local intervention, or noninvasive intervention indicated); Grade 3 = severe (or medically significant but not life-threatening); Grade 4 = life-threatening; Grade 5 = death.
Time frame: 10 weeks
Population: Safety Set, consisting of all randomized subjects who took at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LYC-30937-EC 25 mg PO QD | Number of Subjects With Type of Adverse Events (AEs) Serious Adverse Events (SAEs) and AEs That Led to Discontinuation of Treatment. | Subjects with ≥ 1 TEAE | 22 Participants |
| LYC-30937-EC 25 mg PO QD | Number of Subjects With Type of Adverse Events (AEs) Serious Adverse Events (SAEs) and AEs That Led to Discontinuation of Treatment. | Subjects with ≥ 1 TESAE | 1 Participants |
| LYC-30937-EC 25 mg PO QD | Number of Subjects With Type of Adverse Events (AEs) Serious Adverse Events (SAEs) and AEs That Led to Discontinuation of Treatment. | Subjects with TEAE leading to discontinuation | 0 Participants |
| Placebo PO QD | Number of Subjects With Type of Adverse Events (AEs) Serious Adverse Events (SAEs) and AEs That Led to Discontinuation of Treatment. | Subjects with ≥ 1 TEAE | 27 Participants |
| Placebo PO QD | Number of Subjects With Type of Adverse Events (AEs) Serious Adverse Events (SAEs) and AEs That Led to Discontinuation of Treatment. | Subjects with ≥ 1 TESAE | 3 Participants |
| Placebo PO QD | Number of Subjects With Type of Adverse Events (AEs) Serious Adverse Events (SAEs) and AEs That Led to Discontinuation of Treatment. | Subjects with TEAE leading to discontinuation | 2 Participants |