Clinical Trials Register

Summary
EudraCT Number:	2018-003987-29
Sponsor's Protocol Code Number:	APD334-303
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-12-20
Trial 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

Spain - AEMPS

A.2

EudraCT number

2018-003987-29

A.3

Full title of the trial

An Open-Label Extension Study of Etrasimod in Subjects with Moderately to Severely Active Ulcerative Colitis

Estudio de extensión abierto para evaluar etrasimod cuando se administra a sujetos con colitis ulcerosa activa moderada o grave

A.3.1

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

An Open-Label Extension Study for Treatment of Moderately to Severely Active Ulcerative Colitis

Estudio de extensión abierto para tratamiento de colitis ulcerosa activa moderada o grave

A.3.2

Name or abbreviated title of the trial where available

ELEVATE UC OLE

A.4.1

Sponsor's protocol code number

APD334-303

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	Giles Hulley
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	34912071350
B.5.6	E-mail	mmartinarranz@salud.madrid.org

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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Ulcerative Colitis

Colitis Ulcerosa

E.1.1.1

Medical condition in easily understood language

Ulcerative Colitis a form of inflammatory bowel disease.

Colitis ulcerosa como forma de enfermedad inflamatoria intestinal.

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 safety of long-term administration of etrasimod in subjects with moderately to severely active ulcerative colitis (UC)

Evaluar la eficacia de etrasimod suministrado a largo plazo en sujetos con colitis ulcerosa (CU) activa de moderada a grave

E.2.2

Secondary objectives of the trial

To assess the long-term efficacy of etrasimod in subjects with moderately to severely active UC

Evaluar la eficacia a largo plazo de etrasimod en sujetos con CU activa de moderada a grave

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Must have met the eligibility criteria and have been enrolled in one of the two parent studies (APD334-301 or APD334-302) and also meet the following additional criteria:
a. Subjects previously enrolled in Study APD334-301 must have either:
I. Completed the Week 12 visit and have been assessed to have active UC that had deteriorated from baseline and meet one of the following criteria:
• Absolute RB ≥ 2 on 2-consecutive days, and confirmation of ES ≥ 2 at or after the Week 12 assessment
• Absolute RB + SF ≥ 4 on 2-consecutive days, and confirmation of ES ≥ 2 at or after the Week 12 assessment
• Absolute RB ≥ 2 or RB + SF ≥ 4 (in any order) on 2-consecutive days, and confirmation of ES ≥ 2 at or after the Week 12 assessment
or
II. Completed the Week 52 visit
Note: An endoscopic evaluation is required, however a proctosigmoidoscopy does not need to be repeated if performed within the last 4 weeks
b. Subjects previously enrolled in APD334-302 must have completed the Week 12 visit
2. Eligible women of childbearing potential must fulfill the following:
a. Have a negative urine beta human chorionic gonadotropin (β-hCG) pregnancy test
b. Not breastfeeding
3. 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 who is of childbearing potential must agree to using a highly effective contraception method during treatment and for 4 weeks 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 (complete sexual abstinence defined as refraining from heterosexual intercourse for the entire period of risk associated with study treatments). 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 (calendar, symptothermal, post-ovulation methods) is not acceptable.
c. A male must agree to using condoms during treatment and for 4 weeks following treatment.
4. Ability to provide written informed consent or assent (parent or legal guardian must provide consent for a subject < 18 years of age or as required per local regulations who has assented to participate in the study) and to be compliant with the schedule of protocol assessments. Enrollment of subjects < 18 years should be conducted only if acceptable according to local laws and regulations.

Los sujetos son aptos para inscribirse en este estudio si cumplen TODO lo siguiente:
1. Deben haber cumplido los criterios de idoneidad y haberse inscrito en uno de los dos estudios principales (APD334-301 o APD334-302) y también cumplir los siguientes criterios adicionales:
a. Los sujetos inscritos previamente en el estudio APD334-301 deben:
I. Haber completado la visita de la semana 12 y haber sido evaluados como que presentan CU activa que había empeorado desde el inicio y cumplir uno de los siguientes criterios:
• Recuento absoluto de HR ≥2 en 2 días consecutivos y confirmación de PE ≥2 en o después de la evaluación de la semana 12
• Recuento absoluto de HR + FD ≥4 en 2 días consecutivos y confirmación de PE ≥2 en o después de la evaluación de la semana 12
• Recuento absoluto de HR ≥2 o HR + FD ≥4 (en cualquier orden) en 2 días consecutivos, y confirmación de PE ≥2 en o después de la evaluación de la semana 12
o bien
II. Haber completado la visita de la semana 52
Nota: Se requiere una evaluación endoscópica; sin embargo, no es necesario repetir la proctosigmoidoscopia si se realiza en las últimas 4 semanas.
b. Los sujetos inscritos previamente en APD334-302 deben haber completado la visita de la semana 12
2. Las mujeres en edad fértil aptas deben cumplir lo siguiente:
a. Tener un resultado negativo de gonadotropina coriónica humana beta (GCH-β) en la prueba de embarazo en orina
b. No estar en periodo de lactancia
3. Las mujeres deben cumplir o bien a o bien b de los siguientes criterios, y los hombres deben cumplir el criterio c para ser aptos para el estudio:
a. Las mujeres que no sean fértiles deben cumplir uno de los siguientes criterios:
 Posmenopáusicas, definido como no haber tenido menstruación durante 12 meses sin una causa médica alternativa
 Procedimiento de esterilización permanente, como histerectomía, salpingectomía bilateral u ovariectomía bilateral.
b. Las mujeres en edad fértil deben aceptar utilizar un método anticonceptivo altamente eficaz durante el tratamiento y en las 4 semanas posteriores al tratamiento que alcance una tasa de fallo de menos del 1 % al año cuando se utilice de forma continuada y correcta. A continuación se muestran los que se consideran métodos anticonceptivos altamente eficaces:
 Anticonceptivo hormonal combinado (que contenga estrógeno y progesterona) asociado a la inhibición de la ovulación, que puede ser por vía oral, intravaginal o transdérmica.
 Anticonceptivo hormonal únicamente de progesterona asociado a la inhibición de la ovulación, que puede ser por vía oral, inyectado o implantable.
 Dispositivo intrauterino (DIU).
 Sistema intrauterino de liberación de hormonas.
 Ligadura de trompas bilateral.
 Compañero sometido a vasectomía, siempre y cuando el compañero sea la única pareja sexual de la participante del ensayo mujer en edad fértil y que el compañero haya recibido la evaluación médica del éxito de la operación.
 Abstinencia sexual (abstinencia sexual completa definida como evitar las relaciones sexuales heterosexuales durante todo el periodo de riesgo asociado a los tratamientos del estudio). La fiabilidad de la abstinencia sexual debe evaluarse en relación a la duración del estudio clínico y el estilo de vida habitual y preferido de la participante. La abstinencia periódica (métodos del calendario, sintotérmico y posovulación) no son aceptables.
c. Los hombres deben aceptar utilizar preservativo durante el tratamiento y en las 4 semanas posteriores al tratamiento.
4. Capacidad de proporcionar consentimiento informado por escrito o asentimiento (el progenitor o tutor legal debe dar su consentimiento para un sujeto <18 años que haya dado su asentimiento para participar en el estudio o según lo requerido por las normativas locales) y de cumplir el calendario de evaluaciones del protocolo. La inscripción de los sujetos <18 años solo debe realizarse si es aceptable de acuerdo con las leyes y normativas locales.

E.4

Principal exclusion criteria

Subjects who meet ANY of the following exclusion criteria will NOT be eligible for enrollment into the study:
1. If the Investigator considers the subject to be unsuitable for any reason to participate in the OLE study

Exclusions related to general health:
2. Experienced an adverse event that led to discontinuation from parent etrasimod study
3. Day 1 pre-dose sitting vital sign assessment: heart rate < 50 bpm and systolic BP < 90 mm Hg
4. Day 1 pre-dose 12-lead electrocardiogram (ECG) in the supine position showing a second or third-degree AV block, periods of asystole > 3 seconds, PR interval > 200 ms, or QTcF ≥ 450 ms (males) or QTcF ≥ 470 ms (females)
5. Subjects requiring colectomy during the parent study
6. Subjects requiring treatment with prohibited medications as defined in the parent study

Exclusions related to laboratory results:
7. Laboratory values that meet study treatment discontinuation rules
Note: In the case of any abnormal laboratory results, laboratory tests may be repeated once and if these results are within normal range, the subject is eligible for enrollment.

Los sujetos que cumplan ALGUNO de los siguientes criterios de exclusión NO serán aptos para inscribirse en el estudio:
1. Si el investigador considera que el sujeto sea no apto por cualquier motivo para participar en el estudio de EA
Exclusiones relacionadas con la salud general:
2. Haber sufrido un acontecimiento adverso que haya requerido retirarle del estudio original de etrasimod
3. Evaluación de las constantes vitales en posición sedente en el día 1 antes de la dosis: frecuencia cardíaca <50 lpm y TA sistólica <90 mm Hg
4. Electrocardiograma (ECG) de 12 derivaciones en posición supina en el día 1 antes de la dosis que muestra un bloqueo AV de segundo o tercer grado, periodos de asistolia >3 segundos, intervalo PR >200 ms, o QTcF ≥450 ms (varones) o QTcF ≥470 ms (mujeres)
5. Sujetos que requieran una colectomía durante el estudio original
6. Sujetos que requieran tratamiento con medicamentos prohibidos según se define en el estudio principal
Exclusiones relacionadas con los resultados de laboratorio:
7. Los valores de laboratorio que cumplan las reglas de interrupción del tratamiento del estudio
Nota: En el caso de alguna anomalía en los resultados de laboratorio, las pruebas analíticas se podrán repetir una vez y si estos resultados se encuentran dentro del rango normal, el sujeto es apto para la inscripción.

E.5 End points

E.5.1

Primary end point(s)

• Incidence of treatment-emergent adverse events and serious adverse events (SAEs)
• Incidence and severity of laboratory abnormalities, and change from baseline in laboratory values (hematology, serum chemistry, coagulation, and urinalysis)
• Incidence of vital sign abnormalities and changes from baseline

• Incidencia de acontecimientos adversos surgidos durante el tratamiento y acontecimientos adversos graves (AAG)
• Incidencia e intensidad de las anomalías analíticas y el cambio desde el inicio en los valores de las analíticas (hematología, bioquímica sérica, coagulación y análisis de orina)
• Incidencia de anomalías en las constantes vitales y cambios desde el inicio.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 2, 4, 8, 12, 24, 36, 52, 64, 76, 88, 104, 116, 128, 140, 156, 168, 180, 192, 2018, 220, 232, 244, 260, 2 week Follow-up visit

Semana 2, 4, 8, 12, 24, 36, 52, 64, 76, 88, 104, 116, 128, 140, 156, 168, 180, 192, 2018, 220, 232, 244, 260, 2 semanas visita de seguimiento

E.5.2

Secondary end point(s)

• Proportion of subjects achieving clinical remission at each of the following weeks: Weeks 52, 104, 156, 208, and 260
• Proportion of subjects achieving clinical response at each of the following weeks: Weeks 52, 104, 156, 208, and 260
• Proportion of subjects achieving symptomatic remission at Weeks 52, 104, 156, 208, and 260
• Proportion of subjects achieving non-invasive response at each of the following weeks: Weeks 12, 24, 36, 52, 104, 156, 208, and 260
• Proportion of subjects remaining in clinical remission at the following weeks: Weeks 12, 52, 104, 156, 208, and 260
• Longitudinal change from both OLE and parent study baseline in SF, RB, and SF + RB at each of the following weeks: Weeks 12, 24, 36, 52, 104, 156, 208, and 260
• Proportion of subjects with remission and response using total Mayo Clinic score at each of Weeks 12, 52, and annually thereafter up to Week 260
• Histologic improvement at each visit with endoscopy
• Histologic remission at each visit with endoscopy
• 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, 52, 104, 156, 208, and 260, in subjects with EIMs at baseline.

• Proporción de sujetos que alcanzan remisión clínica en cada una de las siguientes semanas: Semanas 52, 104, 156, 208 y 260
• Proporción de sujetos que consiguen respuesta clínica en cada una de las siguientes semanas: Semanas 52, 104, 156, 208 y 260
• Proporción de sujetos que alcanzan remisión sintomática en las semanas 52, 104, 156, 208 y 260
• Proporción de sujetos que alcanzan una respuesta no invasiva en cada una de las siguientes semanas: Semanas 12, 24, 36, 52, 104, 156, 208 y 260
• Proporción de sujetos con remisión clínica en las siguientes semanas: Semanas 12, 52, 104, 156, 208 y 260
• Cambio longitudinal tanto desde el inicio de la EA como del estudio original en FD, HR y en FD + HR en cada una de las siguientes semanas: Semanas 12, 24, 36, 52, 104, 156, 208 y 260
• Proporción de sujetos con remisión y respuesta mediante la puntuación de la clínica Mayo total en cada una de las semanas 12, 52 y cada año a partir de entonces hasta la semana 260
• Diagnóstico histológico de mejora en cada visita con endoscopia
• Diagnóstico histológico de remisión en cada visita con endoscopia
• Tiempo hasta la pérdida de respuesta, con pérdida de la respuesta definida por:
 aumento de ≥2 puntos desde la semana 12 en las puntuaciones combinadas de FD + HR y una puntuación combinada de FD + HR de ≥4, en 2 visitas consecutivas (≥7 días de diferencia);
 confirmación por la lectura central de la PE ≥2; y
 confirmación de resultado negativo en la prueba de C. difficile.
• Proporción de sujetos con mejora en las MEI en las semanas 12, 52, 104, 156, 208 y 260, en sujetos con MEI en el inicio.

E.5.2.1

Timepoint(s) of evaluation of this end point

Weeks 12, 24, 36, 52, 104, 156, 208, and 260

Semanas 12, 24, 36, 52, 104, 156, 208 y 260

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

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

Última visita Último Paciente

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