Clinical Trials Register

Summary
EudraCT Number:	2016-000708-26
Sponsor's Protocol Code Number:	CFTY720DIT15T
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-06-22
Trial 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-000708-26

A.3

Full title of the trial

Evaluation of clinical response in relation to the immunological status change in RRMS patients treated with Gilenya (fingolimod) for 12 months.

Studio clinico della durata di 12 mesi, per caratterizzare la risposta clinica in correlazione con i cambiamenti dell¿assetto immunologico in pazienti affetti da Sclerosi Multipla recidivante-remittente trattati con Gilenya.

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

A.4.1

Sponsor's protocol code number

CFTY720DIT15T

A.5.4

Other Identifiers

Name:

Number:

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	FONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS UNIVERSITA' CATTOLICA DEL SACRO CUORE
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione Policlinico Universitario A. Gemelli
B.5.2	Functional name of contact point	Unit¿ Operativa Sclerosi Multipla
B.5.3	Address:
B.5.3.1	Street Address	L.go Gemelli 8
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00168
B.5.3.4	Country	Italy
B.5.4	Telephone number	0630155390
B.5.5	Fax number	0635501909
B.5.6	E-mail	dhneurologia@gmail.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 - 0.5 MG - CAPSULE RIGIDE - USO ORALE - BLISTER(PVC/PVDC/ALU) SCATOLA DA 28 CAPSULE
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS EUROPHARM LTD
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Relapsing Remitting Multiple Sclerosis

Sclerosi Multipla Remittente Recidivante

E.1.1.1

Medical condition in easily understood language

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10063399
E.1.2	Term	Relapsing-remitting 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

The study of the immunological profile at baseline and its variation during the early stages of treatment with fingolimod could represent a predictor of clinical response to therapy. In particular, a regulatory pattern of lymphocyte subtypes represented by a higher ratio of regulatory T cells than the effector T cells, may be an optimal response markers during therapy with fingolimod.

Lo studio del profilo immunologico al basale e la sua variazione durante le fasi precoci di trattamento con fingolimod potrebbero rapprentare un fattore predittivo della risposta clinica alla terapia. Nello specifico, un pattern regolatorio dei sottotipi linfocitari rappresentato da un pi¿ alto rapporto delle cellule T regolatorie rispetto alle cellule T effetrici, possa essere un marker di risposta ottimale durante terapia con fingolimod.

E.2.2

Secondary objectives of the trial

To evaluate if it is possible that serum BDNF levels are a biomarker predictive of neurocognitive performance maintenance in patients with Multiple Sclerosis responders to treatment with fingolimod; To investigate a possible relationship between immunological profile at baseline or changes during the early stages of treatment with fingolimod and the incidence rate of infections could be important to better characterize the safety profile of the drug.

valutare se i livelli di BDNF sierico siano un biomarcatore predittivo di mantenimento delle prestazioni neurocognitive nei pazienti con Sclerosi Multipla responder al trattamento con fingolimod. Investigare una possibile relazione tra il profilo immunologico al basale o le sue variazioni durante le fasi precoci di trattamento con fingolimod e il tasso di incidenza di infezioni potrebbe essere importante per caratterizzare meglio il profilo di sicurezza del farmaco.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

They will be included in the study patients male or female aged> 18 years, affected from relapsing remitting multiple sclerosis with high disease activity. Patients will be eligible to treatment with fingolimod according to the data sheet of the drug. In summary, they are deemed eligible for treatment with fingolimod patients belonging to one of the following groups:
1) Patients with high disease activity despite treatment with a beta-interferon. These patients may be defined as those who have not responded to a full and adequate course of therapy (normally at least one year of treatment) of beta-interferon. Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gadolinium-enhancing lesion. Patient non-responders can also be defined as a patient who has, over the previous year, an unchanged or increased relapse rate or who have severe relapses.
2) Patients with severe relapsing-remitting multiple sclerosis rapidly evolving, defined as two or more disabling relapses in one year, and with 1 or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared to a previous RM recently performed. For all therapeutic indications the dose is 0.5 mg orally, once daily.
3) The women of childbearing age will be enrolled only if they make use of highly effective contraceptive measures. The use of contraceptive measures must be extended to male patients with partners of childbearing age.
Highly effective contraceptive measures deemed, under specific CTFG the recommendations are as follows:
_ combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation 1:
o oral
o intravaginal
o transdermal
_ progestogen-only hormonal contraception associated with inhibition of ovulation 1:
o oral
o injectable
o implantable 2
_ intrauterine device (IUD)
_ intrauterine hormone-releasing system ( IUS)
_ bilateral tubal occlusion
_ vasectomised partner
_ sexual abstinence

Saranno inclusi nello studio pazienti di sesso femminile o maschile con età > di 18 anni, con diagnosi di Sclerosi multipla remittente recidivante ad elevata attività di malattia, elegibili al trattamento con fingolimod secondo la scheda tecnica del farmaco. In sintesi, sono ritenuti eleggibili al trattamento con fingolimod i pazienti apparententi ad uno dei seguenti gruppi:
1) Pazienti con un’elevata attività di malattia nonostante la terapia con interferone-beta. Questi pazienti possono essere definiti come coloro che non hanno risposto ad un ciclo terapeutico completo ed adeguato (normalmente almeno un anno di trattamento) con interferone beta. I pazienti devono avere avuto almeno 1 recidiva nell’anno precedente mentre erano in terapia, e presentare almeno 9 lesioni iperintense in T2 alla RM cerebrale o almeno 1 lesione captante gadolinio. Un paziente non responder può anche essere definito come un paziente che presenta, rispetto all’anno precedente, un tasso di recidive invariato o aumentato o che presenta recidive gravi.
2) Pazienti con Sclerosi Multipla recidivante-remittente grave ad evoluzione rapida, definita da due o più recidive disabilitanti in un anno, e con 1 o più lesioni captanti gadolinio alla RM cerebrale o con un aumento significativo del carico lesionale in T2 rispetto ad una precedente RM recentemente effettuata. Per tutte le indicazioni terapeutiche la posologia è di 0,5 mg per os, una volta al giorno.
3) Le donne in età fertile saranno arruolate solo se fanno uso di misure contraccetive altamente efficaci. L’uso di misure contraccettive devono essere estese anche ai pazienti di sesso maschile che hanno partner in età fertile.
Le misure contraccettive ritenute altamente efficaci, in riferimento alle specifiche raccomandazioni del CTFG sono le seguenti:
Pazienti che fanno uso di contraccettivi ormonali combinati (contenenti estrogeni e progesterone ) associati ad inibizione dell’ovulazione sia orali, intravaginali che transdermici
Pazienti che fanno uso di contaccettivi ormonali a base di solo progesterone che inibiscono l’ovulazione , sia orali, iniettabili o impiantabili
Pazienti con posizionamento di IUD (ntrauterine device )
Pazienti con posizionamento di sistemi di rilascio ormonale intrauterini
Pazienti con occlusione bilaterale delle tube
Pazienti con partner vasectomizzato
Pazienti che praticano astinenza sessuale

E.4

Principal exclusion criteria

• Patients with HIV (a specific serologic testing for HIV should be conducted prior to initiating treatment with fingolimod).
Patients who are at increased risk for opportunistic infections, including immunocompromised patients (including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies).
• Patients infected with HBV, HCV and HAV (before starting treatment with Gilenya should be performed the following serological tests: HBsAg, HBcAb, anti HCV antibodies, anti HAV IgM and IgG).
• Patients with latent or active tuberculosis (before starting treatment with Gilenya should be performed dosing Quantiferon test)
• Malignant tumors diagnosed in the active phase.
• Severe hepatic impairment (Child-Pugh Class C).
• Hypersensitivity to the active substance or to any of the excipients.
• Patients treated with live vaccines within 30 days prior to screening
• Women of childbearing potential and not complianti highly effective contraceptive measures defined in accordance with the recommendations of the Clinical Trial Facilitation Group (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf)
• Male patients with partners of childbearing age who do not belong to highly effective contraceptive measures defined in accordance with the recommendations of Clinical Trial Facilitation Group
• Women who are pregnant or breast-feeding (in all women of childbearing age before you start treatment with Gilenya will be made the dosage of beta-HCG in serum, and also will be made a urinary pregnancy test every month during treatment as required by the recommendations of the Clinical Trial Facilitation Group)
• Patients with moderate to severe heart failure (III / IV class according to the New York Heart Association)
• Documented relapse or steroid therapy ev a month before the start of therapy
• Patients who have discontinued treatment with fingolimod following an inadequate response

Pazienti con HIV (un test sierologico specifico per HIV deve essere condotto prima di iniziare il trattamento con fingolimod).
• Pazienti che presentano un aumentato rischio di infezioni opportunistiche, fra cui i pazienti immunocompromessi (inclusi quelli trattati con terapie immunosoppressive concomitanti o quelli immunocompromessi da terapie precedenti).
• Pazienti con infezione da HBV, HCV e HAV (prima di inziare il trattamento con fingolimod devono essere eseguiti i seguenti test sierologici: HbsAg, HbcAb, anticorpi anti HCV, anticorpi anti HAV IgM e IgG).
• Pazienti con tubercolosi latente o attiva (prima di inziare il trattamento con fingolimod devono essere eseguiti il dosaggio del test Quantiferon)
• Tumori maligni in fase attiva diagnosticati.
• Severa compromissione epatica (Child-Pugh classe C).
• Ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti.
• pazienti trattati con vaccini vivi nei 30 giorni precedenti allo screening
• donne potenzialmente fertili e non complianti a misure contraccettive altamente efficaci definite secondo le raccomandazioni del Clinical Trial Facilitation Group (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf)
• pazienti di sesso maschile che hanno partner in età fertile e non complianti a misure contraccettive altamente efficaci definite secondo le raccomandazioni del Clinical Trial Facilitation Group
• donne in gravidanza o allattamento (in tutte le donne in età fertile prima di iniziare il trattamento con fingolimod sarà effettuato il dosaggio della beta-HCG su siero; inoltre sarà effettuato un test di gravidanza urinario mensilmente durante il trattamento come previsto dalle raccomandazioni del Clinical Trial Facilitation Group)
• pazienti con insufficienza cardiaca da moderata a grave (Classe III/IV secondo la New York Heart Association)
• Ricadute documentate o terapia con steroidi ev un mese prima dell’inizio della terapia
• pazienti che hanno precedentemente interrotto il trattamento con fingolimod in seguito a una risposta inadeguata.

E.5 End points

E.5.1

Primary end point(s)

To describe patients response to fingolimod treatment as Treg/Teffector ratio. The ratio will be evaluated at baseline and at the end of the study (12 months) (also intermediate points will be considered at 1 month, 3 months, 6 months, ) and its relative increase will be evaluated. This procedure admit us to take into account the individual variability and the intermediate scheduled evaluation may be a controlled of intraindividual variability which should be not too high with respect to disease changes in the same time observation window.

L’obiettivo primario dello studio è quello di valutare se l’efficacia della risposta al trattamento con fingolimod correla con la variazione del rapporto Treg/Teffetricici ai diversi timepoint dello studio rispetto allo status immunologico al basale. Questo obiettivo sarà raggiunto valutando se la differenza del rapporto tra % Cellule Tregolatorie / % cellule T Effetrici dal basale fino ad un anno di trattamento con fingolimod sia statisticamente significativo tra i pazienti che hanno risposto in modo ottimale e i pazienti che non hanno risposto alla terapia. I pazienti responder sono definiti dai pazienti che non hanno attività clinica e radiologica di malattia. Lo status immunologico sarà inoltra valutato a tempi intermedi , nello specifico a uno, tre e sei mesi dall’inizio della terapia, per cogliere eventuali variabilità immunologiche individuali.

E.5.1.1

Timepoint(s) of evaluation of this end point

0/1/3/6/12 months

0/1/3/6/12 mesi

E.5.2

Secondary end point(s)

To evaluate cognitive functions of patients at the time of starting fingolimod and after 12 months in order to better describe the patient's clinical status and, consequently, the study drug response.
To correlate BDNF production of PBMC with treatment response (responders and suboptimal-responders/non responders) and immunological change status.
To characterize in immunological term, patients who had a major incidence or had more aggressive form of infections in order to establish if is it possible to speculate that a particular change in the immunological repertoire is correlate with safety topics.

La produzione spontanea di BDNF sar¿ misurata mediante test ELISA (Saggio Immuno-Assorbente legato ad un Enzima).
I pazienti saranno sottoposti a valutazione neuropsicologica attraverso un abatteria di test che sar¿ effettuata al basale e dopo 12 mesi dall¿inizio del trattamento.

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months

12 mesi

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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:

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2021-06-22.

Yes

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

F.4.2.2

In the whole clinical trial

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)

clinical practice

normale pratica clinica

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

2016-09-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-21

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

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IMP with orphan designation in the indication
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