Clinical Trials Register

Summary
EudraCT Number:	2013-002622-23
Sponsor's Protocol Code Number:	1301.4
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-04-25
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

2013-002622-23

A.3

Full title of the trial

Safety and Efficacy of BI 695500 in patients with moderately to severely active rheumatoid arthritis: an open-label extension trial

Seguridad y eficacia de BI 695500 en pacientes con artritis reumatoide activa de moderada a grave: ensayo de extensión abierto

A.3.1

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

Safety and Efficacy of BI 695500 in patients with moderately to severely active rheumatoid arthritis: an open-label extension trial

Seguridad y eficacia de BI 695500 en pacientes con artritis reumatoide activa de moderada a grave: ensayo de extensión abierto

A.4.1

Sponsor's protocol code number

1301.4

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	Boehringer Ingelheim International GmbH
B.1.3.4	Country	Germany
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	Boehringer Ingelheim International GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	QRPE PSC CT Information Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	+3493 404 5100
B.5.5	Fax number	+3493404 5580
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.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.3.2	Product code	Bi 695500
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not applicable
D.3.9.1	CAS number	CAS15
D.3.9.2	Current sponsor code	Bi 695500
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	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	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	Yes
D.3.11.13.1	Other medicinal product type	monoclonal antibody

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

moderately to severely active rheumatoid arthritis

Artritis reumatoide activa de moderada a grave

E.1.1.1

Medical condition in easily understood language

moderately to severely active rheumatoid arthritis

Artritis reumatoide activa de moderada a grave

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	16.1
E.1.2	Level	HLT
E.1.2	Classification code	10039075
E.1.2	Term	Rheumatoid arthritis and associated conditions
E.1.2	System Organ Class	100000004870

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
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 long-term safety of BI 695500 in adult patients with moderate to severe active rheumatoid arthritis (RA) who have successfully completed treatment in Trial 1301.1.

Evaluar la seguridad a largo plazo de BI 695500 en pacientes adultos con artritis reumatoide (AR) de moderada a grave que han completado con éxito el tratamiento del ensayo 1301.1.

E.2.2

Secondary objectives of the trial

To assess the long-term efficacy of BI 695500 in patients with moderately to severely active RA. These analyses will be displayed by the groups the patients were randomized in Trial 1301.1 as well as overall.

Evaluar la eficacia a largo plazo de BI 695500 en pacientes con AR activa de moderada a grave. Estos análisis se efectuarán para los grupos aleatorizados de pacientes del ensayo 1301.1 y también en conjunto.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Must give written informed consent and be willing to follow this CTP.
2. Male or female patients, with moderately to severely active RA who have previously participated in the double-blind randomized clinical Trial 1301.1.
3. Current treatment for RA on an outpatient basis:
a) Patients must continue to receive and tolerate oral or parenteral methotrexate (MTX) therapy at a dose of 15-25 mg per week (dose may be as low as 10 mg per week if the patient is unable to tolerate a higher dose). The dose must have been stable for at least 4 weeks prior to Day 1.
b) Patients must be willing to receive oral folic acid (at least 5 mg/week or as per local practice) or folinic acid (at least 1 mg per week or as per local practice) or equivalent during the entire trial (mandatory co-medication for MTX treatment).
c) If receiving current treatment with oral corticosteroids (other than intra-articular or parenteral), the dose must not exceed 10 mg/day prednisolone or equivalent. During the 4 weeks prior to Baseline (Day 1) the dose must remain stable.
d) Intra-articular and parenteral corticosteroids are not permitted throughout the trial, with the exception of IV administration of 100 mg methylprednisolone 30 to 60 minutes prior to each infusion as this is part of the trial procedures.
e) Any concomitant non-steroidal anti-inflammatory drugs (NSAIDs) must be stable throughout the trial.
f) Patients may be taking oral hydroxychloroquine provided that the dose is not greater than 400 mg/day, or chloroquine provided that the dose is not greater than 250 mg/day. These doses must have been stable for a minimum of 12 weeks prior to Day 1. The hydroxychloroquine or chloroquine treatment will need to be continued at a stable dose with the same formulation until the end of the trial.
4. For participants of reproductive potential (males and females), use of a medically acceptable method of contraception during the trial, i.e., a combination of 2 forms of effective contraception (defined as hormonal contraception, intrauterine device, condom with spermicide, etc.). Females of childbearing potential must also agree to use an acceptable method of contraception (see above) for 12 months following completion or discontinuation from the trial medication.

1. Proporcionar el consentimiento informado por escrito y estar dispuesto a seguir este PEC.
2. Ser varón o mujer con AR activa de moderada a grave y haber participado previamente en el ensayo clínico aleatorizado doble ciego 1301.1.
3. Tratamiento ambulatorio actual para la AR:
a) Los pacientes deben continuar recibiendo y tolerando un tratamiento con metotrexato (MTX) administrado por vía oral o parenteral a dosis de entre 15 y 25 mg por semana (las dosis podrán ser de tan solo 10 mg por semana en el caso de que los pacientes no toleren dosis mayores). La dosis debe haber sido estable durante al menos 4 semanas previamente al día 1.
b) Los pacientes deben estar dispuestos a tomar ácido fólico por vía oral (como mínimo, 5 mg/semana o según la práctica local), ácido folínico (como mínimo, 1 mg/semana o según la práctica local) o algún fármaco equivalente durante todo el ensayo (medicación concomitante obligatoria para el tratamiento con MTX).
c) Si el paciente está recibiendo actualmente un tratamiento con corticoesteroides orales (salvo que sean por vía intraarticular o parenteral), la dosis no deberá superar los 10 mg/día de prednisolona o fármaco equivalente. Durante las 4 semanas previas al inicio del ensayo (día 1), la dosis deberá permanecer estable.
d) Los corticoides intraarticulares y parenterales no están permitidos durante el ensayo, excepto la administración i.v. de 100 mg de metilprednisolona de 30 a 60 minutos antes de cada infusión como parte de los procedimientos del ensayo.
e) Cualquier fármaco concomitante antiinflamatorio no esteroideo (FAINE) debe ser estable a lo largo del ensayo.
e) Los pacientes podrán estar tomando hidroxicloroquina por vía oral siempre que la dosis no sea superior a los 400 mg/día o cloroquina siempre que la dosis no sea superior a los 250 mg/día. Estas dosis deben haber sido estables durante como mínimo las 12 semanas previas al día 1. Dicho tratamiento con hidroxicloroquina o cloroquina deberá continuar administrándose a una dosis estable y con la misma formulación hasta el final del ensayo.
4. Los pacientes en edad fértil (varones y mujeres) deberán usar durante todo el ensayo un método anticonceptivo aceptable desde el punto de vista médico, esto es, una combinación de dos métodos anticonceptivos efectivos (definidos como anticonceptivos hormonales, dispositivo intrauterino, preservativo con espermicida, etc.). Las mujeres en edad fértil también deberán comprometerse a utilizar un método anticonceptivo aceptable (véase arriba) durante un periodo de 12 meses tras la finalización o la interrupción de la medicación del ensayo.

E.4

Principal exclusion criteria

1. Patients receiving current treatment with corticosteroids must not be receiving a dose exceeding 10 mg/day prednisone or equivalent.
2. Serious underlying medical conditions, which, per the investigator?s discretion, could impair the ability of the patient to participate in the trial (including but not limited to ongoing severe infection, severe immunosuppression, severe heart failure, uncontrolled hypertension, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease).
3. Pregnancy or breast feeding. For women of childbearing potential, a positive serum pregnancy test at the Screening Visit.
4. Patients who have significant cardiac disease, including but not limited to congestive heart failure of Class III or IV of the New York Heart Association (NYHA) classification; uncontrolled angina or arrhythmia; any uncontrolled or severe cardiovascular or cerebrovascular disease; or uncontrolled hypertension.
5. Treatment with IV or intramuscular corticosteroids. The only exception will be the administration of 100 mg IV methylprednisolone 30 to 60 minutes before each infusion as part of the trial procedures.
6. Any condition or treatment (including biologic therapies) that, in the opinion of the investigator, may place the patient at unacceptable risk during the trial.
7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times upper limit of normal (ULN).
8. Hemoglobin <8.0 g/dL.
9. Levels of IgG <5.0 g/L.
10. Absolute neutrophil count <1500/?L.
11. Platelet count <75000/?L.

1. Los pacientes que estén recibiendo actualmente un tratamiento con corticoesteroides no deben recibir una dosis superior a 10 mg/día de prednisona o fármaco equivalente.
2. Problemas médicos subyacentes graves que, a juicio del investigador, podrían impedir al paciente participar en el ensayo (como, entre otros, infecciones graves en curso, inmunosupresión grave, insuficiencia cardíaca grave, hipertensión no controlada, diabetes mellitus no controlada, úlceras gástricas y enfermedad autoinmune activa).
3. Embarazo y lactancia. Para mujeres en edad fértil, un resultado positivo en la prueba de embarazo en suero en la visita de selección.
4. Pacientes con insuficiencia cardíaca significativa, como insuficiencia cardíaca congestiva de clase III o IV según la clasificación de la Asociación del Corazón de Nueva York (NYHA), arritmia o angina de pecho no controladas, cualquier trastorno cardiovascular o cerebrovascular grave o no controlado o hipertensión no controlada, entre otros.
5. Tratamiento con corticoesteroides administrados por vía i.v. o intramuscular. La única excepción será la administración de 100 mg de metilprednisolona por vía i.v. de 30 a 60 minutos antes de cada infusión como parte de los procedimientos del ensayo.
6. Cualquier tratamiento (incluidos los biológicos) o enfermedad que, según el investigador, puedan suponer un riesgo inaceptable para el paciente durante el ensayo.
7. Aspartato aminotransferasa (ALT) o alanina aminotransferasa (AST) > 2,5 veces el límite superior de la normalidad (LSN).
8. Hemoglobina < 8,0 g/dl.
9. Niveles de IgG < 5,0 g/l.
10. Recuento absoluto de neutrófilos < 1500/?l.
11. Recuento de plaquetas < 75.000/?l.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this trial is defined as the number (proportion) of patients with drug related adverse events during the treatment phase.

El criterio de valoración principal se define como el número (la proporción) de pacientes con AA relacionados con fármacos durante la fase de tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

48 weeks

48 semanas

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
- The change from Baseline in Trial 1301.1 in DAS28 (erythrocyte sedimentation rate [ESR]) at Week 48 of Trial 1301.4;
- The proportion of patients meeting the American College ofRheumatology 20% (ACR20) response criteria (based on improvement since Baseline in Trial 1301.1) at Week 48 of Trial 1301.4;
- The proportion of patients who meet the ACR/European League Against Rheumatism (EULAR) definition of remission (based on improvement since Baseline in Trial 1301.1) at Week 48 of Trial 1301.4;
- The proportion of patients who meet the EULAR response (good response, moderate response, or no response) (based on DAS28 improvement since Baseline in Trial 1301.1) at Week 48 of Trial 1301.4.

Criterios de valoración secundarios
? El cambio en DAS28 (velocidad de sedimentación globular [VSG]) desde la línea de base del ensayo 1301.1 hasta la semana 48 del ensayo 1301.4
? El porcentaje de pacientes que cumplen con los criterios de respuesta ACR20 (basado en el cambio desde la línea de base del ensayo 1301.1) en la semana 48 del ensayo 1301.4
? El porcentaje de pacientes que presentan una remisión según la definición de la ACR/Liga Europea contra el Reumatismo (EULAR) en la semana 48 del ensayo 1301.4 (basado en la mejora desde la línea de base del ensayo 1301.1)
? El porcentaje de pacientes que presentan una respuesta EULAR (buena, moderada o ausencia de respuesta) en la semana 48 del ensayo 1301.4 (basado en la mejora de DAS28 respecto de la línea de base del ensayo 1301.1)

E.5.2.1

Timepoint(s) of evaluation of this end point

week 48

48 semanas

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

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

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.8.3

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

Belgium

Bulgaria

Canada

France

Greece

Ireland

Italy

Netherlands

New Zealand

Norway

Portugal

Sweden

Argentina

Brazil

Chile

Estonia

Germany

Guatemala

Hungary

Spain

Mexico

Peru

Poland

Russian Federation

Serbia

South Africa

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

The trial will be considered to be complete once the last patient on trial meets one of the following (whichever comes first):
? Completes the Week 48 Visit; or
? Is discontinued prior to the Week 48 Visit and has the End of Trial Visit (see above); or
? Completes the SFU phase; or
? Dies; or
? Is lost to follow-up.
The Sponsor may also elect to discontinue clinical investigations under this trial for any reason at any time.

El ensayo se considerará finalizado cuando el último paciente incluido en el ensayo reúna uno de los siguientes requisitos (el que cumpla en primer lugar):
?complete visita semana 48
?abandone ensayo antes de visita semana 48 y acuda a visita FdT (véase más arriba)
?complete fase de seguimiento de seguridad
?fallezca; o
?se pierda contacto para su seguimiento
El promotor también podrá decidir suspender las investigaciones clínicas de este ensayo en cualquier momento y por cualquier motivo.

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:

225

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

123

F.4.2.2

In the whole clinical trial

250

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)

None

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

2014-07-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-23

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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