Clinical Trials Register

Summary
EudraCT Number:	2014-004868-38
Sponsor's Protocol Code Number:	20110186
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-01-13
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

Spain - AEMPS

A.2

EudraCT number

2014-004868-38

A.3

Full title of the trial

A Randomized Withdrawal Double-blind Study of Etanercept Monotherapy Compared to Methotrexate Monotherapy for Maintenance of Remission in Subjects With Rheumatoid Arthritis.

Estudio de retirada de medicación, aleatorizado, doble ciego, de comparación de etanercept en monoterapia frente a metotrexato en monoterapia para el mantenimiento de la remisión en sujetos con artritis reumatoide

A.3.1

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

A study comparing the use of etanercept and methotrexate, used either alone or in combination, for maintaining remission in rheumatoid arthritis.

Estudio para comparar etanercept en monoterapia frente a metotrexato en monoterapia para el mantenimiento de la remisión en sujetos con artritis reumatoide

A.4.1

Sponsor's protocol code number

20110186

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	Amgen 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	Amgen 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	Amgen (EUROPE) GmbH
B.5.2	Functional name of contact point	Medical Information
B.5.3	Address:
B.5.3.1	Street Address	Dammstrasse 23, P.O. Box 1557
B.5.3.2	Town/ city	Zug
B.5.3.3	Post code	CH-6301
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+34900850153
B.5.6	E-mail	MedinfoInternational@amgen.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	Yes
D.2.1.1.1	Trade name	Enbrel
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Enbrel
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ETANERCEPT
D.3.9.1	CAS number	185243-69-0
D.3.9.4	EV Substance Code	SUB01984MIG
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	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Yes
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	Methotrexate
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharmaceuticals
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	methotrexate
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	methotrexate
D.3.9.1	CAS number	59-05-2
D.3.9.2	Current sponsor code	methotrexate
D.3.9.3	Other descriptive name	METHOTREXATE
D.3.9.4	EV Substance Code	SUB08856MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 25
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	Solution for injection in pre-filled syringe
D.8.4	Route of administration of the placebo	Subcutaneous use
D.8 Placebo: 2
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

Rheumatoid arthritis

Artritis reumatoide

E.1.1.1

Medical condition in easily understood language

Rheumatoid arthritis

Artritis reumatoide

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	PT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

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 evaluate the efficacy of etanercept monotherapy compared to methotrexate monotherapy on maintenance of remission in subjects with rheumatoid arthritis who were on etanercept plus methotrexate combination therapy.

Evaluar la eficacia de etanercept en monoterapia en comparación con metotrexato en monoterapia en el mantenimiento de la remisión en sujetos con AR que recibían un tratamiento con etanercept más metotrexato

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of etanercept plus methotrexate therapy compared to methotrexate monotherapy on maintenance of remission.
To evaluate the efficacy of 1) etanercept monotherapy compared to methotrexate monotherapy and 2) etanercept plus methotrexate therapy compared to methotrexate monotherapy on:
- disease activity
- disease worsening and time to disease worsening
- remission and time to recapture remission after rescue treatment

-Evaluar la eficacia del tratamiento de etanercept más metotrexato en comparación con metotrexato en monoterapia en el mantenimiento de la remisión
-Evaluar la eficacia de 1) etanercept en monoterapia en comparación con metotrexato en monoterapia y 2) etanercept más metotrexato en comparación con metotrexato en monoterapia en:
La actividad de la enfermedad
El empeoramiento de la enfermedad y el tiempo hasta el empeoramiento de la enfermedad
La remisión y el tiempo hasta la recuperación de la remisión después de un tratamiento de rescate

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Optional pharmacogenetic sub-study to evaluate the correlation of inherited genetic variations to rheumatoid arthritis and/or responsiveness to etanercept and methotrexate.

Subestudio opcional farmacogenético para evaluar la correlación en las diferencias genéticas hereditarias con la artritis reumatoide y/o respuesta al etarnecept y metotrxato.

E.3

Principal inclusion criteria

In very good RA disease control for ? 6 months in the opinion of the investigator
Receiving treatment with etanercept for RA for ? 6 months prior to run-in visit 1
Receiving treatment with methotrexate of 10 mg to 25 mg weekly for ? 6 months AND on a stable dose of oral methotrexate for ? 8 weeks prior to run-in visit 1
? 18 years of age at screening

- Con un muy buen control de la enfermedad de AR durante ? 6 meses en opinión
del investigador
- En tratamiento con etanercept para la AR durante ? 6 meses antes de la visita de preinclusión 1
-En tratamiento con una dosis de 10 mg a 25 mg de metotrexato una vez a la
semana durante ? 6 meses Y con una dosis estable de metotrexato oral durante
? 8 semanas antes de la visita de preinclusión 1.
- ? 18 años de edad en la selección
-Ver protocolo para el resto de criterios de inclusión.

E.4

Principal exclusion criteria

Subject has known history of alcoholic hepatitis, nonalcoholic steatohepatitis or immunodeficiency syndromes, including Human Immunodeficiency Virus infection.
Subject has any active infection (including chronic or localized infections) for which anti-infectives were indicated within 4 weeks prior to run-in visit 1.
Subject has a serious infection, defined as requiring hospitalization or intravenous anti-infectives within 8 weeks prior to run-in visit 1.
Subject has known alcohol addiction or dependency or uses alcohol daily.
Subject has used biologic DMARD other than etanercept OR has used an oral janus kinase inhibitor ? 6 months prior to run-in visit 1
Subject has one or more significant concurrent medical conditions per investigator judgment

- El sujeto tiene antecedentes conocidos de hepatitis alcohólica, esteatohepatitis
no alcohólica o síndromes de inmunodeficiencia, incluida la infección por el Virus de la Inmunodeficiencia Humana.
- El sujeto ha tenido cualquier infección activa (incluidas infecciones crónicas o
localizadas) para las que se hayan indicado agentes antiinfecciosos durante las
4 semanas previas a la visita de preinclusión 1.
- El sujeto presenta una infección grave, definida como aquella que requiere
hospitalización o agentes antiinfecciosos intravenosos, durante las 8 semanas
previas a la visita de preinclusión 1.
-El sujeto presenta una adicción o dependencia conocidas del alcohol, consume
alcohol a diario o tiene actualmente un consumo o abuso de sustancias.
- El sujeto ha utilizado un FAME distinto de etanercept O ha utilizado un inhibidor
oral de la cinasa Janus ? 6 meses antes de la visita de preinclusión 1.
- El sujeto tiene una o más enfermedades concomitantes significativas según el
criterio del investigador.
- Ver protocolo para el resto de criterios de exclusión.

E.5 End points

E.5.1

Primary end point(s)

Simplified Disease Activity Index (SDAI) remission (? 3.3)

Remisión del índice simplificado de actividad de la enfermedad (SDAI) (?
3,3) en la semana 48

E.5.1.1

Timepoint(s) of evaluation of this end point

week 48

semana 48

E.5.2

Secondary end point(s)

1. SDAI score and change from baseline at all measured timepoints
2. Disease activity score (28 joint) calculated using the erythrocyte sedimentation rate formula (DAS-28-ESR) and change from baseline at all measured timepoints
3. Disease activity score (28 joint) using the C-reactive protein formula (DAS-28-CRP) and change from baseline at all measured timepoints
4. Clinical Disease Activity Index (CDAI) and change from baseline at all measured timepoints
5. SDAI remission (? 3.3) at all measured timepoints
6. Boolean remission at all measured timepoints
7. Disease worsening defined as an SDAI > 3.3 and ? 11 during two consecutive visits at least 2 weeks apart or SDAI > 3.3 and ? 11 on three or more separate visits or SDAI > 11 after randomization
8. Time to disease worsening defined as an SDAI > 3.3 and ? 11 during two consecutive visits at least 2 weeks apart or SDAI > 3.3 and ? 11 on three or more separate visits or SDAI > 11 after randomization
9. In subjects that receive rescue treatment:
? Time to recapture SDAI remission after starting rescue treatment
? SDAI remission at week 48

1-Puntuación SDAI y cambio respecto al valor basal en todos los momentos de valoración
2-Puntuación de actividad de la enfermedad (28 articulaciones) calculada con el uso de la fórmula que incluye la velocidad de sedimentación globular (DAS-28-ESR) y cambio respecto al valor basal en todos los momentos de valoración
3-Puntuación de actividad de la enfermedad (28 articulaciones) con el uso de la fórmula que incluye la proteína C reactiva (DAS-28-CRP) y cambio respecto al valor basal en todos los momentos de valoración
4-Índice clínico de actividad de la enfermedad (CDAI) y cambio respecto al valor basal en todos los momentos de valoración
5-Remisión del SDAI (? 3,3) en todos los momentos de valoración
6-Remisión booleana en todos los momentos de valoración
7-Empeoramiento de la enfermedad definido como SDAI > 3,3 y ? 11 durante dos visitas consecutivas con 2 semanas de diferencia como mínimo o SDAI > 3,3 y ? 11 en tres o másvisitas distintas o SDAI > 11 después de la aleatorización
8-Tiempo hasta el empeoramiento de la enfermedad definido como SDAI > 3,3 y ? 11 durante dos visitas consecutivas con 2 semanas de diferencia como mínimo o SDAI > 3,3 y ? 11 en tres o más visitas distintas o SDAI > 11 después de la aleatorización
9-En los sujetos que reciben un tratamiento de rescate:
-Tiempo hasta la recuperación de la remisión de SDAI después del inicio del tratamiento de rescate
-Remisión de SDAI en la semana 48

E.5.2.1

Timepoint(s) of evaluation of this end point

All subjects:
?SDAI score, Disease activity score [DAS-28-ESR and DAS-28-CRP], Clinical Disease Activity Index, SDAI remission and Boolean remission evaluated Day 1, week 12, 24, 36 and 48 weeks.
?Disease worsening defined as an SDAI > 3.3 and ? 11 during two consecutive visits at least 2 weeks apart or SDAI > 3.3 and ? 11 on three or more separate visits or SDAI > 11 after randomization.
?Time to disease worsening defined as an SDAI > 3.3 and ? 11 during two consecutive visits at least 2 weeks apart or SDAI > 3.3 and ? 11 on three or more separate visits or SDAI > 11 after randomization.

In subjects that receive rescue treatment during the double-blind treatment period:
?Time to recapture SDAI remission after starting rescue treatment
?SDAI remission at week 48

Todos los sujetos:
-Puntuación SDAI, puntuación de actividad de la enfermedad [DAS-28-ESR y DAS-28-CRP], índice clínico de la actividad de la enfermedad, remisión ddel SDAI y remisión booleana evaluadas día 1, semana 12, 24, 36 y 48.
-Empeoramiento de la enfermedad y tiempo hasta el empeoramiento de la enfermedad definidos como SDAI > 3,3 y ? 11 durante dos visitas consecutivas con 2 semanas de diferencia como mínimo o SDAI > 3,3 y ? 11 en tres o más visitas distintas o SDAI > 11 después de la aleatorización
En los sujetos de tratamiento de rescate:
-Tiempo hasta la recuperación de la remisión de SDAI después del inicio del tratamiento de rescate
-Remisión de SDAI en la semana 48

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

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)

Yes

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

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

Canada

United States

E.8.7

Trial has a data monitoring committee

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

End of Study will be the time when the last subject is assessed or receives an intervention for evaluation in the study.

El fin del estudio será el momento en que el último sujeto sea evaluado o reciba una intervención para la evaluación en el estudio.

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

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

526

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

194

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

358

F.4.2.2

In the whole clinical trial

720

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Treatment or care after the subject has ended the participation in the trial will be normal treatment for condition.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-01-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-04

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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