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 when administered for 12 weeks on clinical remission in subjects with moderately to severely active ulcerative colitis (UC). |
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E.2.2 | Secondary objectives of the trial |
Secondary:
The secondary objective is to assess the efficacy of etrasimod when administered for 12 weeks on clinical response, symptomatic response and remission, endoscopic changes, and mucosal healing in subjects with moderately to severely active UC.
Safety:
The safety objective is to assess the safety of etrasimod after daily doses of 2 mg for 12 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 laws and regulations
2. Ability to provide written informed consent or assent (parent or legal guardian must provide consent for a subject < 18 years of age who has assented to participate in the study or as required per local regulations) and to be compliant with the schedule of protocol assessments
Disease-specific inclusion criteria:
3. Diagnosed with UC ≥ 3 months prior to screening. The diagnosis of UC must be confirmed by endoscopic and histologic evidence. The endoscopy and histology report should be present in the source documents; however, if not available, the screening endoscopy and histology may serve as such
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 enrolled.
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 (performed according to local standard) within 12 months before baseline to rule out dysplasia in subjects with pancolitis > 8 years duration or subjects with left-sided colitis > 12 years duration. Subjects without a surveillance colonoscopy within the prior 12 months will have a colonoscopy at screening (ie, in place of screening proctosigmoidoscopy). Any adenomatous polyps must be removed according to routine practice prior to their first dose of study treatment.
7. Demonstrated an inadequate response to, loss of response to, or intolerance to at least 1 of the following therapies as defined below:
Conventional therapy
a. Oral 5 aminosalicylic acid (5 ASA) compounds
b. Corticosteroids
c. Thiopurines
Biologic therapy or JAK inhibitor therapy
a. Antitumor necrosis factor alpha (TNFα) antibodies (eg, infliximab, adalimumab, golimumab, or biosimilars)
b. Anti integrin antibodies (eg, vedolizumab)
c.Interleukin 12/23 antibodies (eg, ustekinumab)
d. JAK inhibitors (eg, tofacitinib)
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
• Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic diarrhea
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 Chronic Kidney Disease 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 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. Nonpregnant 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.
c. A male subject with a pregnant or non-pregnant female of child-bearing 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 the subject is likely to require hospitalization for medical care or surgical intervention of any kind for UC (eg, colectomy) 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 Clostridioides difficile toxin at screening
6. Pregnancy, lactation, or a positive serum β hCG measured during 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 within 6 months of the Screening Visit
• History or presence of :
second-degree or third-degree atrioventricular block, sick sinus syndrome without a functional pacemaker, or periods of asystole for > 3 seconds without an implanted cardiac defibrillator;recurrent symptomatic bradycardia or recurrent cardiogenic syncope
prerandomization vital signs with a heart rate (HR) < 50 bpm OR systolic blood pressure (BP) < 90 mm Hg OR diastolic BP < 55 mm Hg.
prerandomization electrocardiogram (ECG) with PR interval > 200 ms or Fridericia’s corrected QT interval (QTcF) ≥ 450 ms in men or ≥ 470 ms in women
Start, stop, or change in dosage of any anti-arrhythmic drugs (Class I to IV) within 1 week of randomization
9. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) < 70% of predicted values and FEV1/FVC ratio < 0.70 at screening.
10.Uncontrolled diabetes as determined by hemoglobin A1c (HbA1c) > 9% at screening, or subjects with diabetes with significant comorbid conditions such as retinopathy
11. History of macular edema or retinopathy
12.History of active tuberculosis (TB), history of untreated or inadequately treated latent TB infection, active or latent TB infection at screening.
13.A clinically significant active infection (eg, serious and/or atypical) ≤ 28 days prior to randomization, required iv medication ≤ 14 days prior to randomization, or that may worsen if the subject is treated with a drug having immunosuppressant effects
14. Have HIV/acquired immune deficiency syndrome or test positive for HIV antibodies at screening
15. Have acute or chronic hepatitis B infection or test positive for hepatitis B virus (HBV) at screening
16. 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
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 5 years
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 sphingosine 1 phosphate receptor modulators
23. Treatment with a biologic agent within 8 weeks or within 5 elimination half lives prior to randomization
24. Treatment with an investigational therapy within 3 months prior to randomization
25. Treatment with ≥ 3 biologic agents or ≥ 2 biologics plus a JAK inhibitor approved for treatment of UC
26. Treatment with topical rectal 5 ASA, short chain fatty acid enemas, or steroids within 2 weeks of screening or during screening
27. Treatment with methotrexate within 8 weeks of screening or cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMS) within 16 weeks of screening
28. Receipt of a live vaccine within 4 weeks prior to randomization
29. Previous treatment with natalizumab
30. Previous treatment with lymphocyte-depleting therapies
31. Previous treatment with D penicillamine, thalidomide, dimethyl fumarate, or pyrimidine synthesis inhibitors
32. Treatment with IV immune globulin or plasmapheresis within 3 months prior to randomization
33. 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. |
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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 in clinical remission at Week 12 |
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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 12
• The proportion of subjects achieving symptomatic remission at Week 12
• The proportion of subjects with mucosal healing at Week 12
The other secondary endpoints are:
• The proportion of subjects achieving clinical response at Week 12
•The proportion of subjects achieving endoscopic normalization at Week 12
•The proportion of subjects achieving symptomatic remission at Weeks 2, 4, 8
•The proportion of subjects achieving complete symptomatic remission at each study visit (Weeks 2, 4, 8, 12)
•The proportion of subjects achieving noninvasive clinical response at each study visit (Weeks 2,4,8,12)
•The proportion of subjects achieving symptomatic response at each study visit (Weeks 2,4,8,12)
Exploratory efficacy endpoints are:
• The proportion of subjects with remission and response using total Mayo Clinic score at Week 12
• The proportion of subjects with histologic improvement at Week 12 (as defined by the Geboes Index, Robarts Histopathology Index, and Nancy Histologic Index)
• The proportion of subjects with histologic remission at Week 12 (as defined by the Geboes Index, , Robarts Histopathology Index, and Nancy Histologic Index)
• The proportion of subjects with improvement in EIMs at Week 12 in subjects with EIMs at baseline
Other Efficacy Related Endpoints
Health Related Quality of Life
• Scores and change from baseline to Week 12 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
• The proportion of subjects with UC-related hospitalizations
• The proportion of subjects requiring UC-related surgeries, including colectomy
Pharmacokinetics
• Plasma concentrations of etrasimod, and if warranted M3 (AR503641), and other metabolite(s) of interest 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, and if warranted M3 (AR503641), and other metabolite(s) of interest will be assessed from samples collected prior to dosing (trough) at Weeks 2, 4, 8, 12 and the 2-Week and 4-Week Follow-Up visits
Biomarkers
• Change from baseline in level of fecal calprotectin at Weeks 2,4, 8, and 12
• Change from baseline in level of hs CRP at Weeks 2, 4, 8, and 12
• Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, and 12
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 |
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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 | 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
| 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 |
Argentina |
Australia |
Austria |
Belarus |
Belgium |
Bulgaria |
Canada |
Chile |
China |
Croatia |
Czech Republic |
Denmark |
Egypt |
Estonia |
France |
Georgia |
Germany |
Hungary |
India |
Israel |
Italy |
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 |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |