Clinical Trials Register

Summary
EudraCT Number:	2018-003985-15
Sponsor's Protocol Code Number:	APD334-301
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-07-01
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

Germany - BfArM

A.2

EudraCT number

2018-003985-15

A.3

Full title of the trial

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

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 52

A.4.1

Sponsor's protocol code number

APD334-301

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03945188

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	0018582103647
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	SUB171412
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 on clinical remission in subjects with moderately to severely active ulcerative colitis (UC) after 12 and 52 weeks of treatment.

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

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 law 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
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. Corticosteroids
b. Thiopurines
c. Interleukin 12/23 antibodies (eg, ustekinumab)
d. JAK inhibitors
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 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 CKD 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. A 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. The following are considered highly effective birth control methods:
− 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 trial participant and that the vasectomized partner has
received medical assessment of the surgical success.
− Sexual abstinence. The reliability of sexual abstinence needs to be
evaluated in relation to the duration of the clinical study and the
preferred and usual lifestyle of the subject. Periodic abstinence is not
acceptable.
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 subject is likely to require hospitalization for
medical care or surgical intervention for UC within 12 weeks of baseline
Current evidence of fulminant colitis, toxic megacolon or recent history
(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 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 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 within 6 months of Screening
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 implanted cardiac defibrillator
History or presence of recurrent symptomatic bradycardia or recurrent
cardiogenic syncope
Screening & 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 & 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 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 or forced vital capacity < 70%
of predicted values & FEV1/FVC ratio < 0.70 at screening
10. Uncontrolled diabetes determined by hemoglobin A1c (HbA1c) > 9%
at screening, or subjects with diabetes with significant comorbid conditions eg 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. clinically significant active infection ≤ 28 days prior to
randomization, required IV medication ≤ 14 days prior to randomization
or that may worsen
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 hepatitis B
virus at screening (detectable HBV DNA or positive for hep B surface
antigenor negative for HBsAg and positive for antihepatitis B core
antibody in conjunction with detectable HBV DNA, or detectable HBV
DNA)
16. Have current hep C infection or test positive for hep C virus (HCV)
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, including solid tumors and
haematological 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 S1P receptor modulators
23.Treatment with a biologic agent within 8 weeks or within 5
elimination half-lives for a small-molecule agent prior to randomization
24. reatment 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 UC
26.Treatment with topical rectal 5-ASA, short-chain fatty acid enemas,
or steroids within 2 weeks of/or during screening
27.Treatment with methotrexate within 8 weeks of screening or
cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil within 16
weeks of screening
28.Receipt of a live vaccine within 4 weeks before 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 before 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
 The proportion of subjects achieving clinical remission at Week 52

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12 & Week 52

E.5.2

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
The proportion of subjects achieving symptomatic remission at Week 52
The proportion of subjects achieving symptomatic remission at Week 12
Proportion of subjects, who had not been receiving corticosteroids for ≥
12 weeks in the 40-week treatment period, achieving clinical remission
at Week 52 among subjects receiving corticosteroids at study entry
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

E.5.2.1

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

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1