A study evaluating the efficacy and safety of Etrasimod in the treatment of patients with moderately to severely active Ulcerative Colitis

• Register: EUCTR
• Last refreshed on: 2 May 2022
• Main ID: EUCTR2018-003985-15-NL
• Date of registration: 09/07/2019
• Prospective Registration: Yes
• Primary sponsor: Arena Pharmaceuticals Inc.
• Public title: A study evaluating the efficacy and safety of Etrasimod in the treatment of patients with moderately to severely active Ulcerative Colitis
• Scientific title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 52-Week Study to Assess the Efficacy and Safety of Etrasimod in Subjects with Moderately to Severely Active Ulcerative Colitis - ELEVATE UC 52
• Date of first enrolment: 18/09/2019
• Target sample size: 420
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-003985-15
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belarus, Belgium, Bulgaria, Canada, Chile, Colombia, Croatia, Czech Republic, Czechia, 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

Contacts

• Name: Snehal Naik
• Affiliation: Arena Pharmaceuticals, Inc.

• Name: Snehal Naik
• Affiliation: Arena Pharmaceuticals, Inc.

Key inclusion & exclusion criteria

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 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.
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. Oral 5-aminosalicylic acid (5-ASA) compounds
b. Corticosteroids
c. 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)
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 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 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
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 ß 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 to or during Screening period
History or presence of:
Second or third-degree AV block, sick sinus syndrome, or periods of asystole > 3 seconds without a functional pacemaker
recurrent symptomatic bradycardia or recurrent cardiogenic syncope
Screening or W0/Day 1 prerandomization vital signs with a heart rate (HR) < 50 bpm OR systolic blood pressure (BP) < 90 mm Hg OR diastolic BP < 55 mm Hg.
Screening or W0/Day 1 prerandomization ECG with PR interval > 200 ms or Fridericia’s corrected QT interval = 450 ms in men or = 470 ms in women
Start, stop, change, or planned change in dosage of any anti-arrhythmic drugs (Class I to IV) =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 as determined by hemoglobin A1c (HbA1c) > 9% @ screening or subjects with diabetes with significant comorbid conditions such as retinopathy
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. A clinically significant active infection =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 hep B infection or test +ve for hep B virus (HBV) at screening (detectable HBV DNA or positive for hep B surface antigen [HBsAg], 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 (HCV) at screening as defined by positive for hep C antibody and detectable HCV RNA
17. History of 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
20. History of l

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Ulcerative Colitis
MedDRA version: 20.1 Level: LLT Classification code 10045365 Term: Ulcerative colitis System Organ Class: 100000004856
MedDRA version: 20.1 Level: LLT Classification code 10045366 Term: Ulcerative colitis, unspecified System Organ Class: 100000004856

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Intervention(s)

Product Name: Etrasimod
Product Code: APD334
Pharmaceutical Form: Tablet
INN or Proposed INN: etrasimod L-arginine
CAS Number: 1206123-97-8
Current Sponsor code: APD334 L-arginine
Other descriptive name: AR401959 L-arginine
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

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

Secondary Objective: 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.

Main Objective: 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.

Timepoint(s) of evaluation of this end point: Week 12 & Week 52

Secondary Outcome(s)

Secondary end point(s): Key secondary efficacy endpoints:
• 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
• The proportion of subjects in clinical remission at Week 52 and who had not been receiving corticosteroids for = 12 weeks prior to Week 52
• The proportion of subjects with mucosal healing at Week 52
• The proportion of subjects with mucosal healing at Week 12
• The proportion of subjects achieving clinical remission at both Weeks 12 and 52

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

Secondary ID(s)

APD334-301

2018-003985-15-SK

NCT03945188

125154

Source(s) of Monetary Support

Arena Pharmaceuticals Inc.

Ethics review

Status: Approved
Approval date: 18/09/2019
Contact: