Clinical Trials Register

Summary
EudraCT Number:	2011-003484-30
Sponsor's Protocol Code Number:	CFTY720DES03
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:	2012-04-12
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

2011-003484-30

A.3

Full title of the trial

A multi-centre, open-label, non-randomised, parallel group clinical trial to assess the efficacy of fingolimod in naïve patients versus fingolimod in patients previously treated with interferons or glatiramer acetate, based on the presence of relapses in patients with relapsing-remitting multiple sclerosis.

Ensayo clínico, abierto, no aleatorizado, de grupos paralelos, multicéntrico para evaluar la eficacia de fingolimod como terapia en pacientes de novo vs. fingolimod como terapia en pacientes previamente tratados con interferones o acetato de glatirámero, en base a la presencia de brotes, en pacientes con esclerosis múltiple remitente-recurrente.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

Earlims

A.4.1

Sponsor's protocol code number

CFTY720DES03

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 Farmacéutica 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 Farmacéutica S.A.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Trial Form Support
B.5.2	Functional name of contact point	Mireia Fabregas
B.5.3	Address:
B.5.3.1	Street Address	Consell de Cent 334-336
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08009
B.5.3.4	Country	Spain
B.5.4	Telephone number	34931850200
B.5.5	Fax number	34931850200
B.5.6	E-mail	mireia.fabregas@tfscro.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	Gilenya
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilenya
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	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.3.9.2	Current sponsor code	CFTY720
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

Multiple Sclerosis relapsing-remitting course

Esclerosis Múltiple remitente-recurrente

E.1.1.1

Medical condition in easily understood language

Multiple Sclerosis

Esclerosis Múltiple

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluar si el tratamiento de novo con fingolimod 0,5 mg en pacientes con esclerosis múltiple de curso remitente-recurrente de corta evolución (menos de cinco años) es superior en la reducción de la tasa anualizada de brotes con respecto al tratamiento con fingolimod 0,5 mg en pacientes de sus mismas características y tiempo de evolución que sí han presentado tratamientos de primera línea previos.

E.2.2

Secondary objectives of the trial

- Describir el efecto de fingolimod en la atrofia cerebral, mediante cambios en el volumen cerebral, en ambos grupos.
- Comparar la eficacia entre ambos grupos.
- Evaluar la seguridad y tolerabilidad del tratamiento de fingolimod, mediante la evaluación de los acontecimientos adversos (AA), exámenes físicos, constantes vitales, resultados de análisis de laboratorio, resultados de revisiones oftalmológicas y revisiones dermatológicas o electrocardiogramas en ambos grupos.
- Evaluar la calidad de vida relacionada con la enfermedad, mediante la escala PRIMUS en ambos grupos.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients 18 to 50 years of age, inclusive.
2. Patients diagnosed with multiple sclerosis, according to the revised McDonald criteria of 2010,1 with a relapsing-remitting course,2 and with at least 9 T2 lesions consistent with the disease.
3. Patients with a duration greater than or equal to one year and less than or equal to five years.
4. Patients who have had at least two relapses in the past two years.
5. Patients with an EDSS score3 between 0 and 3.5, inclusive.
6. Patients
a. Naïve: patients who have never been treated with a DMT
or
b. Previously treated with first-line DMT patients who have been treated with a first-line DMT at least during one year (interferon ?-1a [IM or SC], interferon-?-1b or glatiramer acetate).
7. Patients who grant their written consent after they have had the nature and purpose of the research explained clearly to them (informed consent in writing).

1. Pacientes de 18 a 50 años, ambos inclusive.
2. Pacientes con diagnóstico de esclerosis múltiple, según criterios revisados de McDonald de 2010 ( ), de curso remitente-recurrente ( ), con al menos 9 lesiones en T2 sugestivas de la enfermedad.
3. Pacientes con una evolución mayor o igual a un año y menor o igual a cinco años.
4. Pacientes que hayan presentado al menos dos brotes en los dos últimos años.
5. Pacientes que presenten una puntuación en la EDSS ( ) de entre 0 y 3,5 ambos valores incluidos.
6. Pacientes
a. Naïve o de novo: pacientes que nunca hayan sido tratados con una TME
o
b. Previamente tratados con TME de primera línea: pacientes que hayan sido tratados como mínimo durante el último año con una TME de primera línea (interferón-β-1a [IM o SC], interferón-β-1b o acetato de glatirámero).
7. Pacientes que otorguen su consentimiento por escrito después de que se les haya explicado claramente la naturaleza y propósito de la investigación (consentimiento informado por escrito).

E.4

Principal exclusion criteria

1. Patients with clinical symptoms of MS different from relapsing-remitting MS.
2. Patients with a history of chronic immune system disease other than MS, such as documented acquired immunodeficiency syndrome (AIDS).
3. Patients with a history of treated or untreated malignant disease of any organ system (except localised basal cell carcinoma of the skin) in the last 5 years, regardless of whether evidence of local relapse or metastasis exists.
4. Patients with uncontrolled diabetes mellitus (HbA1c > 7%).
5. Patients diagnosed with macular oedema during the screening visit. (Patients with a history of macular oedema will be allowed to take part in the study provided that they do not present with macular oedema at the screening visit.)
6. Patients with active systemic bacterial, viral or fungal infections, with documented diagnosis of AIDS, hepatitis B or hepatitis C or who test positive for IgG antibodies against HIV, for hepatitis surface antigen B or for hepatitis C antibodies.
7. Patients who test negative for IgG antibodies against the varicella-zoster virus at the screening visit. Patients may be vaccinated once it is established that they have IgG antibodies and could be included at least 1 month4 after vaccination.
8. Patients who received live or live attenuated vaccines (including varicella-zoster virus or measles virus) in the 2 months prior to the baseline visit.4
9. Patients who received total lymphoid irradiation or bone marrow transplantation in the 2 months prior to the baseline visit.
10. Patients who have received treatment with:
a. Fingolimod at any time, e.g. participation in a fingolimod clinical trial.
b. Immunosuppressant drugs such as azathioprine or methotrexate at any time.
c. Immunoglobulins in the past 6 months.
d. Monoclonal antibodies, including natalizumab, at any time.
e. Cladribine, cyclophosphamide or mitoxantrone at any time.
11. Patients with any unstable medical condition as assessed by the primary treating physician in each centre, e.g. patients with cardiac risk factors (any degree of atrioventricular block, branch block conduction abnormalities or intraventricular conduction block, or patients who have had severe cardiac syncope) or with a slow (bradycardia) or irregular heartbeat.
12. Patients who have taken part in a clinical trial in the last three months.
13. Women of childbearing potential who are planning to become pregnant, are pregnant and/or breastfeeding, or who do not wish to use effective contraception, e.g. hormonal contraceptives (implantation, patches, oral) and double-barrier methods (any double combination of: IUD, male or female condoms with spermicidal gel, diaphragm, contraceptive sponge, cervical cap).
14. Patients with severe hepatic impairment (Child-Pugh class C).

1. Pacientes con manifestación clínica distinta a EM remitente recurrente.
2. Pacientes con antecedentes de enfermedad crónica del sistema inmunológico distinta a EM como el síndrome de inmunodeficiencia adquirida (SIDA) documentado.
3. Pacientes con antecedentes de enfermedad maligna de cualquier sistema orgánico (excepto carcinoma basocelular de la piel localizado) tratada o no tratada, en los últimos 5 años independientemente de si existe evidencia de brote local o de metástasis.
4. Pacientes con diabetes mellitus no controlada (HbA1c >7%).
5. Pacientes con diagnóstico de edema macular durante la visita de selección (se permitirá tomar parte en el estudio a los pacientes con antecedentes de edema macular siempre y cuando no presenten edema macular en la visita de selección).
6. Pacientes con infecciones bacterianas, víricas o fúngicas sistémicas activas, con diagnóstico documentado de SIDA, hepatitis B, hepatitis C o que den positivo en anticuerpos contra el VIH, el antígeno de superficie de hepatitis B o en las pruebas de anticuerpos de hepatitis C.
7. Pacientes negativos para anticuerpos IgG contra el virus varicela-zóster en la visita de selección. Los pacientes pueden ser vacunados y una vez se compruebe que tienen anticuerpos IgG podrían ser incluidos, transcurrido al menos 1 mese desde la vacunación.
8. Pacientes que han recibido vacunas vivas o vivas atenuadas (incluida del virus varicela-zóster o del virus del sarampión) en los 2 meses anteriores a la visita basal ( ).
9. Pacientes que hayan recibido irradiación linfoide total o trasplante de médula ósea en los 2 meses anteriores a la visita basal.
10. Pacientes que hayan recibido tratamiento con:
a. Fingolimod en cualquier momento (por ej. participación en algún ensayo de fingolimod).
b. Medicaciones inmunosupresoras como azatioprina o metotrexato en cualquier momento.
c. Inmunoglobulinas en los últimos 6 meses.
d. Anticuerpos monoclonales (incluyendo natalizumab) en cualquier momento.
e. Cladribina, ciclofosfamida o mitoxantrona en cualquier momento.
11. Pacientes con cualquier condición médicamente inestable, evaluada por el médico tratante principal en cada centro (por ej., pacientes con factores de riesgo cardíacos o con un ritmo lento o irregular del corazón).
12. Pacientes que hayan participado en algún ensayo clínico en los últimos tres meses.
13. Mujeres potencialmente fértiles que tengan previsto quedarse embarazadas, estén embarazadas y/o en periodo de lactancia, o bien que no deseen utilizar un método anticonceptivo eficaz (anticonceptivos hormonales [implantación, parches, oral], y métodos de doble barrera [cualquier combinación doble de: DIU, profilácticos masculinos o femeninos con gel espermicida, diafragma, esponja anticonceptiva, capuchón cervical]).

E.5 End points

E.5.1

Primary end point(s)

To assess whether naïve4 treatment with 0.5 mg fingolimod in patients with short duration relapsing-remitting multiple sclerosis (less than five years) is superior in reducing the annual relapse rate, compared with treatment with 0.5 mg fingolimod in patients with the same disease and duration who have previously received first-line treatments

La evaluación de la variable principal se realizará mediante la determinación de la diferencia en la tasa anualizada de brotes entre ambos grupos de pacientes (pacientes de novo versus pacientes previamente tratados con TME de primera línea).

E.5.1.1

Timepoint(s) of evaluation of this end point

E.5.2

Secondary end point(s)

? To describe the effect of fingolimod on cerebral atrophy through changes in cerebral volume in both groups (naïve patients and patients previously treated with first-line DMTs). Since not all participating centres have the SIENAX software, the analysis of all MRIs will be applicable only for a subpopulation of subjects.
? To compare the efficacy between the two groups (naïve4 patients versus patients previously treated with first-line DMTs) based on:
o Relapse-related variables: time to first relapse after starting treatment; severity of the relapse; percentage of relapse-free patients.
o MRI-related variables: number of T2 active lesions.
o Disability-related variables: change in EDSS score.
? To assess the safety and tolerability of fingolimod treatment by assessing adverse events (AEs), physical examinations, vital signs, laboratory results and results of ophthalmologic examinations or electrocardiograms in both groups (naïve4 patients and patients previously treated with first-line DMTs *1).
? To assess the disease-related quality of life by using the PRIMUS scale in both groups: naïve4 patients and patients previously treated with first-line DMTs.

Describir el efecto de fingolimod en la atrofia cerebral
Comparar la eficacia entre ambos grupos
Variables relacionadas con los brotes
Evaluar la seguridad y tolerabilidad del tratamiento
Variables relacionadas con la discapacidad
Variables relacionadas con la resonancia magnética
Evaluar la calidad de vida relacionada con la enfermedad

E.5.2.1

Timepoint(s) of evaluation of this end point

? To describe the effect of fingolimod on cerebral atrophy

Describir el efecto de fingolimod en la atrofia cerebral

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

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

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

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

Spain

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

n/a

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:

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

F.3.3.1

Women of childbearing potential not using contraception