A study evaluating the efficacy and safety of Etrasimod in the treatment of patients with moderately to severely active Ulcerative Colitis
- Conditions
- lcerative ColitisMedDRA version: 20.1Level: LLTClassification code 10045365Term: Ulcerative colitisSystem Organ Class: 100000004856MedDRA version: 20.1Level: LLTClassification code 10045366Term: Ulcerative colitis, unspecifiedSystem Organ Class: 100000004856Therapeutic area: Diseases [C] - Digestive System Diseases [C06]
- Registration Number
- EUCTR2018-003986-33-CZ
- Lead Sponsor
- Arena Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 330
1. Men, women and adolescents 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 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 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 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 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. Corticosteroids
b. Thiopurines
Biologic therapy or JAK inhibitor therapy
a. Antitumor necrosis factor alpha (TNFa) antibodies (eg, infliximab, adalimumab, golimumab, or biosimilars)
b. Anti-integrin antibodies (eg, vedolizumab)
c. Anti-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
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
1.Severe extensive colitis as evidenced by:
Physician judgement that the subject is likely to require hospitalization for medical care or surgical intervention of any kind for UC (eg,colectomy) within 12w following randomization
Current evidence of fulminant colitis,toxic megacolon or recent history (within last 6 m) of toxic megacolon,or bowel perforation
Previous total or partial colectomy
2.Diagnosis of Crohn’s disease (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 positive serum ß-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 =6 m prior to & during the Screening Period
History or presence of second-degree or third-degree atrioventricular block,sick sinus syndrome,or periods of asystole for >3seconds without a funcional pacemaker
History or presence of recurrent symptomatic bradycardia or recurrent cardiogenic syncope
Screening or W0/D1 prerandomization vital signs with a heart rate <50bpm OR systolic blood pressure <90mm Hg OR diastolic BP<55mm Hg & Screening or W0/D1 prerandomization ECG with PR interval >200ms or Fridericia’s corrected QT interval QTcF=450 ms in men or =470ms in women
Start,stop,change or planned change in dosage of any anti-arrhythmic drugs (Class I to IV) =1w before screening or within 1w b4 or after 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 TB, history of untreated or inadequately treated latent TB infection, active or latent TB infection at screening
13.A clinically significant active infection =28d prior to randomization
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 hep B virus at screening (detectable HBV DNA, or positive for hep B surface antigen, or negative for HBsAg & positive for antihepatitis B core antibody in conjunction with detectable HBV DNA)
16.Have current hep C infection or test positive for hep C virus
17.History of an opportunistic infection or a 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 and hematological malignancies (except basal cell ∈ situ squamous cell carcinomas of the skin that have been excised and resolved) or colonic mucosal dys
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To assess the efficacy of etrasimod when administered for 12 weeks on clinical remission in subjects with moderately to severely active ulcerative colitis (UC).;Secondary Objective: Secondary:<br>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.<br><br>Safety:<br>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.<br><br>Other:<br>Other objectives include evaluation of etrasimod pharmacokinetics (PK) and the effect of etrasimod on health related subject reported outcomes and biomarkers.;Primary end point(s): The primary efficacy endpoints will evaluate etrasimod versus placebo in:<br>• The proportion of subjects achieving clinical remission at Week 12;Timepoint(s) of evaluation of this end point: Week 12
- Secondary Outcome Measures
Name Time Method Timepoint(s) of evaluation of this end point: Weeks 2, 4, 8, and 12 and 2 & 4 weeks follow-up;Secondary end point(s): The key secondary efficacy endpoints are:<br>• The proportion of subjects achieving endoscopic improvement at Week 12<br>• The proportion of subjects achieving symptomatic remission at Week 12<br>• The proportion of subjects with mucosal healing at Week 12<br><br>The other secondary endpoints are:<br>The proportion of subjects achieving clinical response at Week 12<br>• The proportion of subjects achieving endoscopic normalization at Week 12<br>• The proportion of subjects achieving symptomatic remission at Weeks 2, 4, 8<br>• The proportion of subjects achieving complete symptomatic remission at each study visit (Weeks 2, 4, 8, 12)<br>• The proportion of subjects achieving noninvasive clinical response at each study visit (Weeks 2, 4, 8, 12)<br>• The proportion of subjects achieving symptomatic response at each study visit (Weeks 2, 4, 8, 12)