E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Ulcerative Colitis a form of inflammatory bowel disease. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045365 |
E.1.2 | Term | Ulcerative colitis |
E.1.2 | System Organ Class | 100000004856 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045366 |
E.1.2 | Term | Ulcerative colitis, unspecified |
E.1.2 | System Organ Class | 100000004856 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
to assess the efficacy of etrasimod on clinical remission in subjects with moderately to severely active ulcerative colitis (UC) after 12 and 52 weeks of treatment. |
|
E.2.2 | Secondary objectives of the trial |
Secondary:
The secondary objective is to assess the efficacy of etrasimod on clinical response, symptomatic response and remission, endoscopic changes, corticosteroid-free remission, and mucosal healing in subjects with moderately to severely active UC at time points up to 52 weeks of treatment.
Safety:
The safety objective is to assess the long-term safety of etrasimod after daily doses of 2 mg for up to 52 weeks in subjects with moderately to severely active UC.
Other:
Other objectives include evaluation of etrasimod pharmacokinetics (PK) and the effect of etrasimod on health-related subject-reported outcomes and biomarkers. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men or women 16 to 80 years of age, inclusive, at the time of assent/consent. Enrollment of subjects < 18 years should be conducted only if acceptable according to local law and regulations
2. Ability to provide written informed consent or assent and to be compliant with the schedule of protocol assessments
3. Diagnosed with UC ≥ 3 months prior to screening confirmed by endoscopic and histologic evidence
4. Active UC confirmed by endoscopy with ≥ 10 cm rectal involvement. Subjects with proctitis only at baseline who meet the other eligibility criteria for inclusion, including the endoscopic and rectal bleeding criteria for moderate to severe disease, will be capped at 15% of the total subjects
5. Moderately to severely active UC defined as MMS of 4 to 9, including an ES of ≥ 2 and RB score ≥ 1
6. Received a surveillance colonoscopy within 12 months before baseline. Subjects without a surveillance colonoscopy within the prior 12 months will have a colonoscopy at screening (ie, in place of screening proctosigmoidoscopy).
7. Demonstrated an inadequate response to, loss of response to, or intolerance to at least 1 of the following therapies:
a. Corticosteroids
b. Thiopurines
Biologic therapy or JAK inhibitor therapy
a. Antitumor necrosis factor alpha (TNFα) antibodies
b. Anti-integrin antibodies
c. JAK inhibitors
Concomitant treatments:
8. Subjects are permitted to be receiving a therapeutic dose of the following drugs:
- Oral 5-ASA compounds provided the dose has been stable for ≥ 2 weeks immediately prior to randomization
- Oral corticosteroid therapy (prednisone at a stable dose ≤ 20 mg/day, budesonide at a stable dose ≤ 9 mg/day, or equivalent steroid provided the dose has been stable for the 4 weeks immediately prior to the screening endoscopy assessment
- Immunosuppressive agents such as oral azathioprine or 6-mercaptopurine must be discontinued ≥ 2 weeks prior to randomization
- Probiotics (eg, Culturelle®, Saccharomyces boulardii) provided the dose has been stable for the 2 weeks immediately prior to randomization
- Antidiarrheal (eg, loperamide, diphenoxylate with atropine) for control of chronic diarrhea
If oral aminosalicylates or corticosteroids have been recently discontinued, they must have been stopped for at least 2 weeks prior to the endoscopy used for the baseline MMS.
9. Vital signs at screening and pre randomization taken in the sitting position: heart rate ≥ 50 bpm, systolic blood pressure (BP) ≥ 90 mm Hg, and diastolic BP ≥ 55 mm Hg
10.Screening and pre randomization 12-lead electrocardiogram (ECG) showing no clinically significant abnormalities
11.Adequate hematological function defined by white blood cell count ≥ 3.5 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte count ≥ 0.8 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 8 g/dL
12.Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 3.0 × ULN. Subjects with an isolated total bilirubin and normal AST and ALT diagnosed with Gilbert’s syndrome may participate
13. Adequate renal function defined by an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 by the CKD-EPI equation at screening
14. Females must meet either a or b of the following criteria and males must meet criterion c to qualify for the study:
a. A female who is not of childbearing potential must meet 1 of the following:
− Postmenopausal, defined as no menses for 12 months without an alternative medical cause;
− Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.
b. A female who is of childbearing potential must agree to using a highly effective contraception method during treatment and for 4 weeks following treatment that can achieve a failure rate of less than 1% per year when used consistently and correctly. The following are considered highly effective birth control methods:
− Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, which may be oral, intravaginal, or transdermal
− Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injected, or implanted
− Intrauterine device (IUD)
− Intrauterine hormone-releasing system
− Bilateral tubal occlusion
− Vasectomized partner, provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success.
− Sexual abstinence. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject. Periodic abstinence is not acceptable.
c. A male must agree to using condoms during treatment and for 4 weeks following treatment |
|
E.4 | Principal exclusion criteria |
1. Severe extensive colitis as evidenced by:
- Physician judgment that the subject is likely to require hospitalization for medical care or surgical intervention of any kind for UC within 12 weeks of baseline
- Current evidence of fulminant colitis, toxic megacolon or recent history (within last 6 months) of toxic megacolon, or bowel perforation
- Previous total or partial colectomy
2. Diagnosis of CD or indeterminate colitis or the presence or history of a fistula consistent with CD
3. Diagnosis of microscopic colitis, ischemic colitis, or infectious colitis
4. Hospitalization for exacerbation of UC requiring intravenous (IV) steroids within 12 weeks of screening
5. Positive assay or stool culture for pathogens or positive test for Clostridium difficile toxin at screening
6. Pregnancy, lactation, or a positive serum β-hCG measured during screening
7. Clinically relevant hematologic, hepatic, neurological, pulmonary, ophthalmological, endocrine, metabolic, psychiatric, or other major systemic disease making implementation of the protocol or interpretation of the study difficult or would put the subject at risk
8. Recent history (within 6 months of the Screening Visit) of cardiovascular disease, including myocardial infarction, unstable angina, stroke/transient ischemic attack, decompensated heart failure (requiring inpatient treatment), or New York Heart Association class III/IV heart failure
9. Any history of the following, unless treated with an implanted pacemaker or an implanted cardioverter-defibrillator with pacing:
- History or presence of symptomatic bradycardia
- History of sick sinus syndrome or neurocardiogenic syncope
- Second or third-degree AV block
- Periods of asystole > 3 seconds
10. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) < 70% of predicted values & FEV1/FVC ratio < 0.70 at screening
11. Uncontrolled diabetes as determined by hemoglobin A1c (HbA1c) > 9% at screening, or subjects with diabetes with significant comorbid conditions such as retinopathy
12. History of macular edema or retinopathy
13. Current or past history of active tuberculosis (TB), history of untreated latent TB infection, or test positive for latent TB infection at screening.
14. Known active bacterial, viral, fungal, mycobacterial infection, or other infection or any major episode of infection that required hospitalization or treatment with IV antibiotics within 30 days of screening or during screening or oral antibiotics within 14 days prior to screening.
15. Have human immunodeficiency virus (HIV)/acquired immune deficiency syndrome or test positive for HIV antibodies at screening
16. Have acute or chronic hepatitis B infection or test positive for hepatitis B virus (HBV) at screening, or negative for HBsAg and positive for antihepatitis B core antibody in conjunction with detectable HBV DNA, or detectable HBV DNA)
17. Have current hepatitis C infection or test positive for hepatitis C virus (HCV) at screening as defined by positive for hepatitis C antibody and detectable HCV RNA
18. History of an opportunistic infection or serious bacterial, viral, or fungal infections and requiring IV medication(s) ≤ 3 weeks prior to randomization
19. History of or currently active primary or secondary immunodeficiency
20. History of cancer within the last 5 years, including solid tumors and haematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been excised and resolved) or colonic mucosal dysplasia
21. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma
22. History of alcohol or drug abuse within 1 year prior to randomization
23. Hypersensitivity to etrasimod or any of the excipients or placebo compounds
24. Prior treatment with S1P receptor modulators
25. Treatment with a biologic agent within 8 weeks or within 5 elimination half-lives for a small-molecule agent, prior to randomization
26. Treatment with an investigational therapy within 3 months prior to randomization
27. Treatment failure with ≥ 3 biologic agents or ≥ 2 biologics plus a JAK inhibitor approved for treatment of UC
28. Treatment with topical rectal 5-ASA, short-chain fatty acid enemas, or steroids within 2 weeks of screening or during screening
29. Treatment with cyclosporine, tacrolimus, sirolimus, methotrexate, or mycophenolate mofetil (MMF) within 16 weeks of screening
30. Receipt of a live vaccine within 4 weeks prior to randomization
31. Previous treatment with natalizumab
32. Previous treatment with lymphocyte-depleting therapies
33. Previous treatment with D-penicillamine, leflunomide, or thalidomide
34. Treatment with IV immune globulin or plasmapheresis, within 3 months prior to randomization
35. Chronic use of therapies that moderately/strongly inhibit/induce cytochrome P450 (CYP) 2C8 and 2C9 metabolism and inhibitors of UGT1A7 within 4 weeks prior to randomization |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoints will evaluate etrasimod versus placebo in:
The proportion of subjects in clinical remission at Week 12
The proportion of subjects in clinical remission at Week 52 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints are:
The proportion of subjects achieving endoscopic improvement at Week 52
The proportion of subjects achieving endoscopic improvement at Week 12
Proportion of subjects, who had not been receiving corticosteroids for ≥ 12 weeks prior to the end of the study (Week 52), with clinical remission at Week 52
Proportion of subjects with mucosal healing at Week 52
Proportion of subjects with mucosal healing at Week 12
Proportion of subjects achieving clinical remission at both Weeks 12 and 52
The other secondary endpoints are:
Proportion of subjects with a clinical response at Week 52
Proportion of subjects with a clinical response at Week 12
Proportion of subjects with endoscopic normalization at Week 52
Proportion of subjects with endoscopic normalization at Week 12
Proportion of subjects with symptomatic remission at Week 52
Proportion of subjects with symptomatic remission at Week 12
Proportion of subjects with non invasive clinical response at Weeks 12, 16, 20, 24, 32, 40, 48, and 52
Proportion of subjects with symptomatic response at Weeks 12, 16, 20, 24, 32, 40, 48, and 52
Proportion of subjects with remission at Week 52 and corticosteroid-free since Weeks 16, 24, 32, 40, and 48
Proportion of subjects with clinical remission at Week 52 among subjects in clinical response at Week 12
Proportion of subjects achieving clinical response at both Weeks 12 and 52
Proportion of subjects achieving mucosal healing at both Weeks 12 and 52
Proportion of subjects achieving endoscopic normalization at both Weeks 12 and 52
Proportions of subjects with clinical response of RB and SF symptom outcomes at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52
Proportions of subjects with clinical remission of RB and SF symptom outcomes at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52
Exploratory efficacy endpoints are:
Proportion of subjects with remission and response using total Mayo Clinic score at Week 12
Proportion of subjects with remission and response using total Mayo Clinic score at Week 52
Proportion of subjects with histologic improvement at Week 12 (as defined by the Geboes, Robarts, and Nancy histopathology scores)
Proportion of subjects with histologic improvement at Week 52 (as defined by the Geboes, Robarts, and Nancy histopathology scores)
Proportion of subjects with histologic remission at Week 12 (as defined by the Geboes, Robarts, and Nancy histopathology scores)
Proportion of subjects with histologic remission at Week 52 (as defined by the Geboes, Robarts, and Nancy histopathology scores)
Time to loss of response, with loss of response defined by:
A ≥ 2-point increase from Week 12 in the combined SF + RB scores and combined SF + RB score of ≥ 4, on 2 consecutive visits (≥ 7 days apart), and
Confirmed by centrally read ES ≥ 2 and,
Confirmation of negative C. difficile testing
Proportion of subjects with improvement in EIMs at Weeks 12 and 52, in subjects with EIMs at baseline
Other Efficacy-Related Endpoints
Health-Related Quality of Life
Scores and change from baseline at Weeks 12 and 52 in the following:
IBDQ total score
UC-PRO/SS
SF-36, version 2, physical and mental component and domain scores
WPAI-UC
Urgency NRS
Abdominal pain NRS
Proportion of subjects with UC-related hospitalizations
Proportion of subjects requiring UC-related surgeries, including colectomy
Pharmacokinetics
Plasma concentrations of etrasimod, M3 (AR503641), and other metabolite(s) of interest (if warranted) will be assessed from samples collected prior to dosing and 4 hours (± 15 minutes) post-dose (after 12-lead ECG) on Week 0/Day 1
Plasma concentrations of etrasimod, M3 (AR503641), and other metabolite(s) of interest (if warranted) will be assessed from samples collected prior to dosing (trough) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52
Biomarkers
Change from baseline in level of fecal calprotectin at Weeks 4, 8, 12, 24, and 52
Change from baseline in level of hs-CRP at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52
Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52
Safety Endpoints
Incidence and severity of adverse events
Incidence and severity of laboratory abnormalities, and change from baseline in laboratory values (to include hematology, serum chemistry, coagulation, and urinalysis)
Incidence of clinically significant vital sign abnormalities and changes from baseline |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 253 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Belarus |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
China |
Colombia |
Croatia |
Czech Republic |
Denmark |
Egypt |
Estonia |
France |
Georgia |
Germany |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Latvia |
Lebanon |
Lithuania |
Mexico |
Moldova, Republic of |
Netherlands |
Poland |
Portugal |
Romania |
Russian Federation |
Serbia |
Slovakia |
South Africa |
Spain |
Switzerland |
Taiwan |
Thailand |
Turkey |
Ukraine |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |