Clinical Trials Register

Summary
EudraCT Number:	2022-004331-23
Sponsor's Protocol Code Number:	FNO-RS1-TERIFIN
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2023-01-17
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

Czechia - SUKL

A.2

EudraCT number

2022-004331-23

A.3

Full title of the trial

The importance of therapeutic monitoring of teriflunomide and fingolimod in the treatment of multiple sclerosis

Význam terapeutického monitorování teriflunomidu a fingolimodu při léčbě roztroušené sklerózy

A.3.1

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

Monitoring of drugs used in the treatment of multiple sclerosis

Sledování léčiv užívaných při léčbě roztroušené sklerózy

A.3.2

Name or abbreviated title of the trial where available

TERIFIN

A.4.1

Sponsor's protocol code number

FNO-RS1-TERIFIN

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	Fakultní nemocnice Ostrava
B.1.3.4	Country	Czechia
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	Fakultní nemocnice Ostrava
B.4.2	Country	Czechia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fakultní nemocnice Ostrava
B.5.2	Functional name of contact point	Ivana Kacířová
B.5.3	Address:
B.5.3.1	Street Address	17.listopadu 1790/5
B.5.3.2	Town/ city	Ostrava
B.5.3.3	Post code	70852
B.5.3.4	Country	Czechia
B.5.4	Telephone number	+420597374391
B.5.6	E-mail	ivana.kacirova@fno.cz

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	Aubagio 14MG TBL FLM
D.2.1.1.2	Name of the Marketing Authorisation holder	sanofi-aventis groupe
D.2.1.2	Country which granted the Marketing Authorisation	Czechia
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	Aubagio 14MG TBL FLM
D.3.4	Pharmaceutical form	Tablet
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	Teriflunomide
D.3.9.1	CAS number	108605-62-5
D.3.9.4	EV Substance Code	SUB25218
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	14
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.IMP: 2
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 0,5MG CPS DUR
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	Czechia
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	Gilenya 0,5MG CPS DUR
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 HYDROCHLORIDE
D.3.9.1	CAS number	162359-56-0
D.3.9.3	Other descriptive name	Fingolimod hydrochloride
D.3.9.4	EV Substance Code	SUB30967
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

roztroušená skleróza

E.1.1.1

Medical condition in easily understood language

multiple sclerosis

roztroušená skleróza

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	LLT
E.1.2	Classification code	10064137
E.1.2	Term	Progression of multiple sclerosis
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

correlation of the measured concentrations of fingolimod (including the fingolimod-phosphate metabolite) and teriflunomide (including the free fraction) with the clinical status of patients with MS

korelace naměřených koncentrací fingolimodu (včetně metabolitu fingolimod-fosfátu) a
teriflunomidu (včetně volné frakce) s klinickým stavem pacientů s RS

E.2.2

Secondary objectives of the trial

- objectification of adherence to fingolimod and teriflunomide treatment
- possible introduction of TDM fingolimod and teriflunomide into routine clinical practice

- objektivizace adherence k léčbě fingolimodem a teriflunomidem
- případné zavedení TDM fingolimodu a teriflunomidu do rutinní klinické praxe

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) patients diagnosed with MS, taking fingolimod or teriflunomide for at least 6 months
2) men and women older than 18 years
3) signing the Informed Consent to participate in the study

1) pacienti s diagnózou RS, užívající fingolimod nebo teriflunomid alespoň 6 měsíců
2) muži i ženy starší 18 let
3) podpis Informovaného souhlasu s účastí ve studii

E.4

Principal exclusion criteria

1) pediatric patients
2) refusal to sign the Informed Consent to participate in the study, including consent
with genetic testing
3) refusal of blood samples performed beyond standard examinations

1) pacienti v dětském věku
2) odmítnutí podepsání Informovaného souhlasu s účastí ve studii včetně souhlasu
s genetickým vyšetřením
3) odmítnutí krevních vzorků prováděných nad rámec standardních vyšetření

E.5 End points

E.5.1

Primary end point(s)

1) correlation of the measured concentrations of fingolimod (including the metabolite fingolimod-phosphate) and teriflunomide (including the free fraction) with the clinical status of patients with MS
2) objectification of adherence to fingolimod and teriflunomide treatment
3) possible introduction of TDM fingolimod and teriflunomide into routine clinical practice

1) korelace naměřených koncentrací fingolimodu (včetně metabolitu fingolimod-fosfátu) a
teriflunomidu (včetně volné frakce) s klinickým stavem pacientů s RS
2) objektivizace adherence k léčbě fingolimodem a teriflunomidem
3) případné zavedení TDM fingolimodu a teriflunomidu do rutinní klinické praxe

E.5.1.1

Timepoint(s) of evaluation of this end point

obtaining all the necessary data after completing the study

získání všech potřebných údajů po ukončení studie

E.5.2

Secondary end point(s)

1) analysis of the relationship between the measured concentrations of fingolimod (including the fingolimod-phosphate metabolite) and teriflunomide (including the free fraction) with the concentrations of other MS biomarkers, such as plasma neurofilament light chains (“pNfL”) concentrations, vitamin D concentrations, and immune system cell concentrations, which are associated with MS
2) analysis of the relationship between the measured concentrations of fingolimod (including the metabolite fingolimod-phosphate) and teriflunomide (including the free fraction) with the results of the examination of the genetic polymorphism of the protein inhibitor Zinc Finger MIZ-1 (ZMIZ1) in patients taking fingolimod and the genetic polymorphism of the efflux transporter BCRP (ABCG2) and
of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) in patients receiving teriflunomide

1) analýza vztahu naměřených koncentrací fingolimodu (včetně metabolitu fingolimod-
fosfátu) a teriflunomidu (včetně volné frakce) s koncentracemi dalších biomarkerů RS, jako
je koncentrace lehkých řetězců plasmatických neurofilament (“pNfL”), koncentrace
vitamínu D a koncentrace buněk imunitního systému, které jsou spojeny s RS
2) analýza vztahu naměřených koncentrací fingolimodu (včetně metabolitu fingolimod-
fosfátu) a teriflunomidu (včetně volné frakce) s výsledky vyšetření genetického
polymorfismu proteinového inhibitoru Zinc Finger MIZ-1 (ZMIZ1) u pacientů užívajících
fingolimod a genetického polymorfismu efluxního transportéru BCRP (ABCG2) a
mitochondriálního enzymu dihydroorotátdehydrogenázy (DHODH) u pacientů užívajících
teriflunomid

E.5.2.1

Timepoint(s) of evaluation of this end point

obtaining all the necessary data after completing the study

získání všech potřebných údajů po ukončení studie

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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.8.5

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

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:

150

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

150

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)

Participants in the study will be patients who are already taking fingolimod or teriflunomide. Any adjustment or change of medication will be carried out based on the clinical condition of the patient and the decision of the attending physician.

Účastníky studie budou pacienti, kteří již užívají fingolimod nebo teriflunomid. Případná úprava, respektive změna medikace bude prováděna na základě klinického stavu pacienta a rozhodnutí ošetřujícího lékaře.

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

2023-02-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-03-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-11-04

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