Clinical Trials Register

Summary
EudraCT Number:	2012-000835-18
Sponsor's Protocol Code Number:	CFTY720D2306E1
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:	2012-11-29
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

2012-000835-18

A.3

Full title of the trial

Open-label, single-arm extension study to the double-blind, randomized, multicenter, placebo-controlled, parallel-group study comparing the efficacy and safety of 0.5 mg FTY720 administered orally once daily versus placebo in patients with primary progressive multiple sclerosis

Estudio de extensión abierto con un único brazo de tratamiento del estudio multicéntrico, aleatorizado, doble ciego, controlado con placebo, con grupos paralelos para comparar la eficacia y seguridad de 0,5 mg FTY720 administrado por vía oral una vez al día versus placebo en pacientes con esclerosis múltiple primaria progresiva

A.3.1

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

A study to evaluate how safe and effective 0.5 mg FTY720 is in delaying disability progression if taken once daily, in patients with PPMS

Un estudio para evaluar la seguridad y eficacia de 0,5 mg de FTY720 en retrasar la progresión de la discapacidad si se toma una vez al día, en pacientes con EMPP

A.3.2

Name or abbreviated title of the trial where available

efficacy and safety of 0.5 mg fingolimod in patients with primary progressive multiple sclerosis

eficacia y seguridad de 0,5 mg fingolimod en pacientes con esclerosis múltiple progresiva primaria

A.4.1

Sponsor's protocol code number

CFTY720D2306E1

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	Novartis Farmaceutica S.A.
B.1.3.4	Country	Spain
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	Novartis Pharma Service AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Framaceutica S.A.
B.5.2	Functional name of contact point	Oficina de informacion de ee cc
B.5.3	Address:
B.5.3.1	Street Address	Gran Via de les corts catalanes, 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34933064342
B.5.5	Fax number	+34933064290
B.5.6	E-mail	eecc.novartis@novartis.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	GYLENIA 0,5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	Fingolimod
D.3.2	Product code	FTY720D
D.3.4	Pharmaceutical form	Capsule, hard
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	Fingolimod
D.3.9.1	CAS number	162359- 56-0
D.3.9.2	Current sponsor code	FTY720D
D.3.9.3	Other descriptive name	FTY720
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	0.5
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

Primary progressive multiple sclerosis.

Esclerosis multiple primaria progresiva

E.1.1.1

Medical condition in easily understood language

a chronic autoimmune disease which attacks the central nervous system with a steady worsening of neurologic functioning, but without any distinct relapses or periods of remission

una enfermedad crónica autoinmune que ataca el sistema nervioso central con un empeoramiento constante de funcionamiento neurológico, pero sin recaídas distintas o periodos de remisión

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.1
E.1.2	Level	PT
E.1.2	Classification code	10063401
E.1.2	Term	Primary progressive multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system 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 assess the long-term safety, tolerability, and efficacy (as measured by clinical and MRI parameters of disease activity) of fingolimod 0.5 mg/day in PPMS patients.

Para evaluar la seguridad a largo plazo, tolerabilidad y eficacia (medida por parámetros clínicos y de IRM de actividad de la enfermedad) de fingolimod 0,5 mg / día en pacientes con EMPP.

E.2.2

Secondary objectives of the trial

none

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients eligible for inclusion in this study have to fulfill all of the following criteria:
Patients who have provided written informed consent
Patients initially randomized to fingolimod 1.25 mg or placebo as part of the first study cohort, who have completed at least 3 years on study drug treatment at the time of extension study initiation
Patients initially randomized to fingolimod 0.5 mg or placebo as part of the second study cohort who have continued on study drug treatment until such time as the last ongoing patient enrolled in the study has reached 3 years in study.

Los pacientes elegibles para la inclusión en este estudio tienen que cumplir todos los criterios siguientes:
Los pacientes que han escrito el consentimiento informado
Los pacientes inicialmente asignados al azar a fingolimod 1,25 mg o placebo como parte de la cohorte de estudio en primer lugar, que han completado al menos 3 años en el tratamiento del fármaco del estudio en el momento de iniciar el estudio de extensión
Los pacientes inicialmente asignados al azar a fingolimod 0,5 mg o placebo como parte de la cohorte segundo estudio que se han seguido en el tratamiento del fármaco en estudio hasta el momento en que el paciente continua pasado participaron en el estudio se ha llegado a 3 años de estudio.

E.4

Principal exclusion criteria

Patients who meet any of the following exclusion criteria at the baseline visit will not be
eligible for enrollment in the extension study:
1. active chronic disease (or stable but treated with immune therapy) of the immune system other than MS (e.g., rheumatoid arthritis, scleroderma, Sjogren?s syndrome, Crohn?s disease, ulcerative colitis) or with a known immunodeficiency syndrome (HIV-antibody
positive, AIDS, hereditary immune deficiency, drug-induced immune deficiency)
2. active systemic bacterial, viral or fungal infections
3. uncontrolled diabetes mellitus (HbA1c>7%)
4. positive screening for serological markers for hepatitis A, B, C, and E indicating acute or chronic infection:
? anti-hepatitis A virus IgM,
? hepatitis B surface antigen and/or anti-hepatitis B core antigen IgM,
? anti-hepatitis C virus IgG or IgM,
? anti-hepatitis E virus IgM (positive IgG: do hepatitis E virus-RNA polymerase chain reaction; if negative, patient can be included)
Note: The following patients, assuming they have normal aminotransferase activities, can be included in the trial:
? those testing positive for hepatitis B surface antibody, indicating hepatitis B immunization -OR-
? those testing positive for anti-hepatitis B core antigen IgG, indicating a cured hepatitis B -OR-
? those testing positive for anti-hepatitis A virus IgG, indicating a cured hepatitis A
5. macular edema at baseline
6. treatment with Class Ia or III antiarrhythmic drugs (e.g. amiodarone, bretylium, sotalol, ibulitide, azimilide, dofelitide)
7. any of the following cardiovascular conditions:
? myocardial infarction within the past 6 months prior to enrollment or current unstable ischemic heart disease
? cardiac failure at time of Screening (Class III, according to NYHA Classification;
Appendix 2) or any severe cardiac disease as determined by the investigator
? second degree AV block Mobitz type II or a third degree AV block on screening ECG
? an increased QTc (Fridericia and Bazett) interval >500 ms on Screening ECG
? hypertension, uncontrolled by medication
8. any of the following pulmonary conditions:
? severe respiratory disease or pulmonary fibrosis
? active tuberculosis
? reduction of FEV1, FVC and/or DLCO below 60% of core study baseline values or if
FEV1, FVC and/or DLCO at extension study baseline is the second of two consecutive pulmonary function tests with values <80% of core study baseline
9. any of the following hepatic conditions:
? total or conjugated bilirubin greater than the upper limit of the normal range, unless in context of Gilbert?s syndrome
? two consecutive alkaline phosphatase (AP) values greater than 3 times the upper limit of the normal range
? two consecutive AST (SGOT), ALT (SGPT) values greater than 3 times the upper limit of the normal range
? two consecutive gamma-glutamyl-transferase (GGT) values greater than 3 times the upper limit of the normal range
10. any medically unstable condition, as assessed by the primary treating physician
11. participation in any clinical research study other than CFTY720D2306 evaluating another investigational drug or therapy within 6 months prior to extension baseline
12. Pregnant or nursing (lactating) women where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ml).
13. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are using highly effective contraception during the study and for 2 months after stopping treatment. ?Highly effective contraception? defined as contraception which results in less that 1% unwanted pregnancies when used properly according to the label.
Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to baseline. In the case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
Note: If a patient fails on one or more laboratory (or other) assessment criteria, the assessment(s) may be repeated at the discretion of the investigator provided the assessments
are completed within one month.

Los pacientes que cumplan alguno de los siguientes criterios de exclusión en la visita inicial no será
elegible para la inscripción en el estudio de extensión:
1. enfermedad crónica activa (o estable pero tratados con la terapia inmune) del sistema inmune que no es MS (por ejemplo, artritis reumatoide, esclerodermia, síndrome de Sjogren, enfermedad de Crohn, colitis ulcerosa) o con un síndrome conocido inmunodeficiencia (VIH-anticuerpo
positiva, la deficiencia de SIDA, hereditario inmune, inducida por drogas deficiencia inmune)
2. activos sistémicos infecciones bacterianas, virales o fúngicas
3. diabetes mellitus no controlada (HbA1c> 7%)
4. detección positiva para marcadores serológicos para hepatitis A, B, C, y E, que indica infección aguda o crónica:
? anti-virus de la hepatitis A IgM,
? hepatitis B antígeno de superficie y / o anti-hepatitis B IgM antígeno del núcleo,
? anti-hepatitis C virus IgG o IgM,
? anti-hepatitis E virus IgM (IgG positivo: hacer hepatitis E virus de ARN-reacción en cadena de la polimerasa, en caso negativo, el paciente puede ser incluido)
Nota: Las siguientes pacientes, suponiendo que tienen las actividades normales de transaminasas, pueden ser incluidos en el ensayo:
? los que dieron positivo para el anticuerpo de superficie de hepatitis B, hepatitis B indica la inmunización-O-
? los que dieron positivo para anticuerpos anti-hepatitis B antígeno core IgG, lo que indica una hepatitis B curado-O-
? los que dieron positivo para anticuerpos anti-IgG virus de la hepatitis A, lo que indica un curado hepatitis A
5. edema macular basal
6. tratamiento con fármacos de clase Ia o III antiarrítmicos (por ejemplo, amiodarona, bretilio, sotalol, ibulitide, azimilide, dofelitide)
7. cualquiera de las condiciones cardiovasculares siguientes:
? Infarto de miocardio en los últimos 6 meses anteriores a la inscripción o corriente cardiopatía isquémica inestable
? Insuficiencia cardiaca en el momento del examen (Clase III, según la NYHA Clasificación;
Apéndice 2) o cualquier enfermedad cardíaca grave como se determina por el investigador
? en segundo grado Bloqueo AV Mobitz tipo II o de tercer grado Bloqueo AV sobre el cribado del ECG
? un aumento del intervalo QTc (Bazett y Fridericia) intervalo de> 500 ms sobre el cribado del ECG
? hipertensión no controlada por la medicación
8. cualquiera de las condiciones pulmonares siguientes:
? Enfermedad respiratoria grave o fibrosis pulmonar
? tuberculosis activa
? reducción del FEV1, FVC y / o DLCO inferior al 60% de los valores centrales del estudio de línea de base o si
FEV1, FVC y / o DLCO al inicio del estudio de extensión es la segunda de las dos pruebas consecutivas con valores de función pulmonar <80% del valor basal núcleo estudio
9. cualquiera de las condiciones hepáticas siguientes:
? bilirrubina total o conjugado mayor que el límite superior del rango normal, a menos que en el contexto de síndrome de Gilbert
? dos fosfatasa consecutivo alcalina (AP) Los valores mayores que 3 veces el límite superior del rango normal
? dos consecutivos AST (SGOT), ALT (SGPT) Los valores superiores a 3 veces el límite superior del rango normal
? dos consecutivos gamma-glutamil-transferasa (GGT) los valores mayores que 3 veces el límite superior del rango normal
10. cualquier condición médica inestable, según la evaluación del médico de atención primaria
11. participación en cualquier estudio de investigación clínica que no sea CFTY720D2306 evaluar otro fármaco en investigación o terapia dentro de los 6 meses anteriores a la línea de base de extensión
12. Embarazadas o lactantes (lactancia), las mujeres que el embarazo se define como el estado de una mujer después de la concepción y hasta la terminación de la gestación, confirmado por una prueba de laboratorio positiva hCG (> 5 mUI / ml).
13. Las mujeres en edad fértil, que se define como todas las mujeres fisiológicamente capaces de quedar embarazadas, a menos que estén utilizando métodos anticonceptivos altamente efectivos durante el estudio y durante 2 meses después de interrumpir el tratamiento. 'Anticoncepción altamente eficaz "se define como la anticoncepción que se traduce en menos del 1% de embarazos no deseados cuando se usan correctamente de acuerdo a la etiqueta.
Las mujeres son consideradas post-menopáusica y no de riesgo de embarazo si han tenido 12 meses de natural (espontáneo) amenorrea con un perfil clínico apropiado (por ejemplo, edad apropiada, la historia de los síntomas vasomotores) o ha tenido una ooforectomía quirúrgica bilateral (con o sin histerectomía) o ligadura de trompas por lo menos seis semanas antes del inicio del estudio. En el caso de la ooforectomía solo, sólo cuando el estado de reproducción de la
mujer ha sido confirmado por el seguimiento de la evaluación de los niveles hormonales se considera que no en edad fértil.

E.5 End points

E.5.1

Primary end point(s)

long-term safety, tolerability, and efficacy

seguridad a largo plazo, la tolerabilidad y eficacia

E.5.1.1

Timepoint(s) of evaluation of this end point

Physical examination,Vital signs, Blood pressure, laboratory evaluations - All visits:
Electrocardiogram, baseline, monthly through month 3, every 6 months afterwards);
Dermatological and Ophthalmic examinations and Pulmonary Function Tests, yearly;
EDSS, 9HPT and 25TWT every 6 months;
MRI parameters, yearly.

El examen físico, signos vitales, presión arterial, evaluaciones de laboratorio - Todas las visitas:
Electrocardiograma, línea de base, mensual por 3 meses, cada 6 meses después);
Exámenes dermatológicos y oftálmicos y pruebas de función pulmonar al año;
EDSS, 9HPT y 25TWT cada 6 meses;
Parámetros de resonancia magnética, anualmente

E.5.2

Secondary end point(s)

none

E.5.2.1

Timepoint(s) of evaluation of this end point

none

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

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Health-related quality of life
Patient reported outcomes PRIMUS and MSWS12.

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

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

Australia

Belgium

Canada

Czech Republic

Denmark

Finland

France

Germany

Hungary

Italy

Netherlands

Poland

Spain

Sweden

Switzerland

Turkey

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

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:

750

F.1.3

Elderly (>=65 years)

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

522

F.4.2.2

In the whole clinical trial

750

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)

Patients who complete the study on study drug, may be offered access to fingolimod, under a separate protocol, until the drug is available on the market for the treatment of PPMS or the development is discontinued.

Los pacientes que completaron el estudio el fármaco en estudio, se puede ofrecer acceso a fingolimod, bajo un protocolo separado, hasta que el medicamento esté disponible en el mercado para el tratamiento de EMPP o el desarrollo de la interrumpe.

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

2013-01-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-11

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2015-05-13

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