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 |
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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 |
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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. |
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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. |
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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 c. Anti-Interleukin 12/23 antibodies (eg, ustekinumab) d. 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 If oral 5-ASA 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. 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 10.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 ≤ 2.0 × ULN. Subjects with an isolated total bilirubin and normal AST and ALT diagnosed with Gilbert's syndrome may participate 11. Adequate renal function defined by an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 by the CKD epidemiology collaboration equation at screening 12. 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 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. Non pregnant female of childbearing potential must agree to using a highly effective contraception method during treatment and for 30 days 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 subject 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 subject with a pregnant or non-pregnant female of childbearing potential partner must agree to using condoms during treatment and for 30 days following treatment |
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E.4 | Principal exclusion criteria |
1.Severe extensive colitis as evidenced by Physician judgment that subject is likely to require hospitalization for medical care or surgical intervention for UC within 12w following randomization Current evidence of fulminant colitis, toxic megacolon or recent history (last 6months) 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 IV steroids within 12w of screening 5.Positive assay or stool culture for pathogens or positive test for Clostridioides difficile toxin at screening 6.Pregnancy, lactation or a +ve serum β-hCG at screening 7.Clinically relevant neurological, endocrine, metabolic, psychiatric, cognitive impairment, alcohol/drug abuse/dependence or other major systemic disease making implementation of the protocol or interpretation of the study difficult or would put the subject at risk 8.Have any of the following conditions or receiving treatments that may affect cardiovascular function Myocardial infarction, unstable angina, stroke/transient ischemic attack, decompensated heart failure requiring hospitalization or Class III/IV heart failure ≤ 6m prior or during Screening period History or presence of second-degree or third-degree atrioventricular block, sick sinus syndrome or periods of asystole for > 3 seconds without functional pacemaker History or presence of recurrent symptomatic bradycardia or recurrent cardiogenic syncope Screening or W0/Day 1 prerandomization vital signs with a heart rate <50bpm OR systolic blood pressure <90mm Hg OR diastolic BP <55mm Hg Screening or W0/Day 1 prerandomization ECG with PR interval >200ms or Fridericia's corrected QT interval ≥450ms in men or ≥470ms in women Start, stop, change or planned change in dosage of any anti-arrhythmic drugs (Class I to V) ≤1w b4 screening or within 1w b4 or after randomization 9.Forced expiratory volume @ 1 second or forced vital capacity <70% of predicted values & FEV1/FVC ratio <0.70 at screening 10.Uncontrolled diabetes determined by hemoglobin A1c (HbA1c) >9% @screening or subjects with diabetes with significant comorbid conditions 11.History of macular edema or retinopathy 12.History of active tuberculosis, history of untreated or inadequately treated latent TB infection, active or latent TB infection at screening 13.clinically significant active infection ≤28d prior to randomization, required IV medication ≤14d prior to randomization or that may worsen 14.Have HIV/acquired immune deficiency syndrome or test positive for HIV antibodies 15. Have acute or chronic hep B infection or test positive for hepatitis B virus at screening (detectable HBV DNA or positive for hepB surface antigenor negative for HBsAg & positive for antihepatitis B core antibody in conjunction with detectable HBV DNA or detectable HBV DNA) 16. Have current hepC infection or test +ve for hepC virus (HCV) 17. History of an opportunistic infection or history of disseminated herpes simplex or disseminated herpes zoster 18. History of or currently active primary or secondary immunodeficiency 19. History of cancer within the last 5y including solid tumors & haematological malignancies (except basal cell & in situ squamous cell carcinomas of the skin that have been excised and resolved) or colonic mucosal dysplasia 20. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder or multiple myeloma 21. Hypersensitivity to etrasimod or any of the excipients or placebo compounds 22. Prior treatment with S1P receptor modulators 23. Treatment with a biologic agent ≤8w or a small molecule agent ≤5 elimination half-lives & detectable drug level prior to randomization 24. Treatment with an investigational therapy ≤3m prior to randomization 25. Treatment with ≥ 3 biologic agents or ≥ 2 biologics plus a JAK inhibitor approved for UC 26. Treatment with topical rectal 5-ASA, short-chain fatty acid enemas, or steroids ≤2w prior to & during screening 27. Treatment with topical rectal traditional medicine (eg, Chinese medicine), herb enemas or suppositories ≤2w prior to randomization 28. Treatment with methotrexate ≤8w prior to & during screening or cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil ≤16w prior to & during screening 29. Receipt of live vaccine ≤4w before randomization 30. Previous treatment with natalizumab 31. Previous treatment with lymphocyte-depleting therapies 32. Previous treatment with D-penicillamine, thalidomide, dimethyl fumarate or pyrimidine synthesis inhibitors 33. Treatment with IV immune globulin or plasmapheresis, ≤3m prior to randomization 34. Chronic use of therapies that moderately/strongly inhibit/induce cytochrome P450 (CYP) 2C8 & 2C9 metabolism & inhibitors of UGT1A7 ≤ 4w before randomization |
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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 achieving clinical remission at Week 12 The proportion of subjects achieving clinical remission at Week 52 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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 The proportion of subjects achieving symptomatic remission at Week 52 The proportion of subjects achieving symptomatic remission at Week 12 Proportion of subjects in clinical remission at w52 & who had not been receiving corticosteroids for ≥12 weeks prior to w52 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 |
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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, 52 and 2 & 4 weeks follow-up |
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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 | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
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 |
Australia |
Chile |
Colombia |
Egypt |
Georgia |
Lebanon |
Mexico |
Moldova, Republic of |
Serbia |
South Africa |
Thailand |
Turkey |
Estonia |
Argentina |
Austria |
Belarus |
Belgium |
Bulgaria |
Canada |
Croatia |
Czechia |
Denmark |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Latvia |
Lithuania |
Netherlands |
Poland |
Portugal |
Romania |
Russian Federation |
Slovakia |
Spain |
Switzerland |
Taiwan |
Ukraine |
United Kingdom |
United States |
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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
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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 |