Clinical Trials Register

Summary
EudraCT Number:	2012-000835-18
Sponsor's Protocol Code Number:	CFTY720D2306E1
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-06-19
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

France - ANSM

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

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

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

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 Pharma AG
B.1.3.4	Country	Switzerland
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 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 Pharma AG
B.5.2	Functional name of contact point	Information&Communication Médicales
B.5.3	Address:
B.5.3.1	Street Address	2 et 4 rue Lionel Terray
B.5.3.2	Town/ city	Rueil-Malmaison
B.5.3.3	Post code	92500
B.5.3.4	Country	France
B.5.4	Telephone number	+33155476600
B.5.5	Fax number	+33155476100
B.5.6	E-mail	icm.phfr@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	Gilenya
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.

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

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	16.0
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.

E.2.2

Secondary objectives of the trial

Not applicable

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.

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.

E.5 End points

E.5.1

Primary end point(s)

long-term safety, tolerability, and efficacy

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.

E.5.2

Secondary end point(s)

Not applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable

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:

700

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

700

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.

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

2012-12-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-10-24

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

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