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: 4 April 2022
• Main ID: EUCTR2018-003985-15-RO
• Date of registration: 30/03/2022
• Prospective Registration: No
• 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: 03/10/2019
• Target sample size: 372
• 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

Australia, Austria, Belarus, Belgium, Brazil, Bulgaria, Canada, China, Croatia, Czech Republic, Czechia, Denmark, Estonia, France, Georgia, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Latvia, 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: Giles Hulley
• Affiliation: Arena Pharmaceuticals, Inc.

• Name: Giles Hulley
• 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
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. 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
? 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.Eligible women of childbearing potential must be:
a. Non pregnant, evidenced by a negative serum beta-human chorionic gonadotropin (ß-hCG) pregnancy test at screening and a urine dipstick pregnancy test at Day 1
b. Not breastfeeding
15.Both men and women subjects agree to use a highly effective method of birth control throughout the entire study period, from informed consent through the adverse even
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 ß-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 2 months of the Screening Visit) of cardiovascular disease, including myocardial infarction or unstable angina
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 (eg, pneumocystis carinii, cryptococcal meningitis, progressive multifocal leukoencephalopathy) or serious bacterial, viral, or fungal infections (eg, disseminated herpes simplex, disseminated herpes zoster) 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 reso

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

Health Condition(s) or Problem(s) studied

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

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

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)

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.

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

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): 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

Timepoint(s) of evaluation of this end point: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Secondary ID(s)

APD334-301

125154

2018-003985-15-SK

Source(s) of Monetary Support

Arena Pharmaceuticals Inc.

Ethics review

Status: Approved
Approval date: 03/10/2019
Contact: