Clinical Trials Register

Summary
EudraCT Number:	2018-003986-33
Sponsor's Protocol Code Number:	APD334-302
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-09-17
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2018-003986-33

A.3

Full title of the trial

A Phase 3, Randomized, Double Blind, Placebo Controlled, 12 Week Study to Assess the Efficacy and Safety of Etrasimod in Subjects with Moderately to Severely Active Ulcerative Colitis

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.3.2

Name or abbreviated title of the trial where available

ELEVATE UC 12

A.4.1

Sponsor's protocol code number

APD334-302

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03996369

A.5.4

Other Identifiers

Name:

IND number

Number:

125154

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Arena Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Arena Pharmaceuticals Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Arena Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Snehal Naik
B.5.3	Address:
B.5.3.1	Street Address	6154 Nancy Ridge Drive
B.5.3.2	Town/ city	San Diego - CA
B.5.3.3	Post code	92121
B.5.3.4	Country	United States
B.5.4	Telephone number	001 858 210 3647
B.5.6	E-mail	snaik@arenapharm.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Etrasimod
D.3.2	Product code	APD334
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	etrasimod L-arginine
D.3.9.1	CAS number	1206123-97-8
D.3.9.2	Current sponsor code	APD334 L-arginine
D.3.9.3	Other descriptive name	AR401959 L-arginine
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Ulcerative Colitis

E.1.1.1

Medical condition in easily understood language

Ulcerative Colitis, a form of inflammatory bowel disease.

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

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

E.1.3

Condition being studied is a rare disease

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).

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.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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 (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. A female of childbearing potential must agree to using a highly effective contraception method during treatment, and for 30 days following treatment. The following are considered highly effective birth control methods include:
- 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 and that the vasectomized partner has received medical assessment of the surgical success
- Sexual abstinence (complete sexual abstinence defined as refraining from heterosexual intercourse for the entire period of risk associated with study treatments).
c. A male must agree to using condoms during treatment and for 4 weeks following treatment.

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 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 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
History or presence of recurrent symptomatic bradycardia or recurrent cardiogenic syncope
Screening and Day 1 prerandomization vital signs with a heart rate < 50 bpm OR systolic blood pressure < 90 mm Hg OR diastolic BP < 55 mm Hg & Screening and Day 1 prerandomization 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 ≤ 28 days 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 and positive for antihepatitis B core antibody in conjunction with detectable HBV DNA)
16. Have current hepatitis C infection or test positive for hepatitis C virus (HCV)
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 5 years, including solid tumors and hematological malignancies (except basal cell and 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 sphingosine 1 phosphate receptor modulators
23. Treatment with a biologic agent within 8 weeks or 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
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 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, or 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.

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

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12

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
• Proportion of subjects with mucosal healing at Week 12

The other secondary endpoints are:
• 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)

E.5.2.1

Timepoint(s) of evaluation of this end point

Weeks 2, 4, 8, and 12 and 2 & 4 weeks follow-up

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

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

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

Brazil

Bulgaria

Canada

Chile

China

Colombia

Croatia

Czech Republic

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

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1