Clinical Trials Register

Summary
EudraCT Number:	2017-004846-31
Sponsor's Protocol Code Number:	386022010017
National Competent Authority:	Slovenia - JAZMP
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-12-05
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

Slovenia - JAZMP

A.2

EudraCT number

2017-004846-31

A.3

Full title of the trial

Impact of vitamin D supplementation in patients with multiple sclerosis

Vpliv nadomeščanja vitamina D pri bolnikih z multiplo sklerozo

A.3.1

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

Vitamin D supplementation in patients with multiple sclerosis

Nadomeščanje vitamina D pri bolnikih z multiplo sklerozo

A.4.1

Sponsor's protocol code number

386022010017

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	University medical centre Maribor
B.1.3.4	Country	Slovenia
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	University medical centre Maribor
B.4.2	Country	Slovenia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Centre Maribor
B.5.2	Functional name of contact point	Neurology Department
B.5.3	Address:
B.5.3.1	Street Address	Ljubljanska ulica 5
B.5.3.2	Town/ city	Maribor
B.5.3.3	Post code	2000
B.5.3.4	Country	Slovenia
B.5.4	Telephone number	+386(0)2321 2364

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	Oleovit D3 14.400 IU/ml oral drops, solution
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Kabi d.o.o. Austria
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Oral drops, solution
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	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

Relapsing remitting multiple sclerosis

Recidivno remitentna multipla skleroza

E.1.1.1

Medical condition in easily understood language

Multiple sclerosis characterized by clearly defined attacks of new or increasing neurologic symptoms. These attacks are followed by periods of partial or complete recovery (remissions).

Multipla skleroza, ki poteka z jasnimi zagoni bolezni, med katerimi so obdobja delne ali popolne povrnitve (remisije).

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	20.1
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

Vitamin D is important risk factor for developing multiple sclerosis (MS) and for disease progression. Patients with MS who had lower vitamin D levels were at increased risk for more clinical attacks and faster disease progression. It was also shown that patients with MS had lower vitamin D levels in serum than heathy controls. It is not clearly defined, which are the levels of vitamin D in serum, that are high enough to trigger immunomodulatory effect and are safe for patients.
This double-blind randomised clinical trial was designed to compare impact of vitamin D supplemetation in two different doses (1000 IU/day vs 4000 IU/day) in patients with relapsing remitting MS. The main goal of this trial is to show, which dose triggers immunomodulatory effect and it will be suitable for patients with MS to use during winter time, when the vitamin D levels are especially low. To define immunomodulatory response different laboratory, clinical and genetic tests will be performed.

Vitamin D je pomemben dejavnik tveganja za nastanek in potek multiple skleroze (MS). Bolniki z MS, ki so imeli nižje vrednosti vitamina D v krvi, so utrpeli več kliničnih zagonov in hitrejši progres bolezni. Ti bolniki imajo že v osnovi nižje vrednosti vitamina D v krvi kot zdrava populacija. Kljub vsem raziskavam pa še vedno ni jasno, kateri je tisti nivo vitamina D v serumu, ki sproži imunomodulatorni učinek in je hkrati varen za bolnike.
Ta randomizirana dvojno slepa raziskava je bila zasnovana z namenom, da primerja vpliv nadomeščanja vitamina D v dveh različnih odmerkih (1000IU/dan in 4000IU/dan) pri bolnikih z recidivno remitentno obliko MS. Glavni cilj je dokazati, kateri od teh dveh odmerkov je tisti, ki sproži imunomodulatorni učinek in bi bil primeren za nadomeščanje tekom zimskih mesecev, ko so vrednosti vitamina D v krvi bolnikov z MS še posebej nizke. Za dokaz imunomodulatornega učinka bomo uporabili različne laboratorijske, klinične in genetske teste.

E.2.2

Secondary objectives of the trial

The secondary objectives of this clinical trial are to:
• measure basic level of vitamin D in serum in patients with MS during winter time,
• perform the genotypization of selected SNP's and try to determine pharmacogenomic linkage with effect of vitamin D supplementation,
• measure gene expression of products of Th17 cells and their co-factors,
• measure microRNA expression (miR-155) before and after vitamin D supplementation.

Drugi cilji raziskave so:
• izmeriti osnovni nivo vitamina D pri bolnikih z MS v zimskem času,
• opraviti genotipizacijo iz znanstvene literature izbranih SNP-jev in ugotoviti farmakogenomsko povezavo z odzivom na terapijo z nadomeščanjem vitamina D;
• izmeriti izražanje genov, ki so ključni v delovanju produktov Th17 celic in njihovih kofaktorjev,
• izmeriti izražanje miR-155 pred in po terapiji z nadomeščanjem vitamina D.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Relapsing remitting MS
• Treatment with immunomodulatory drug
• Age 18-60 years and
• EDSS score less than 5.

• Recidivno remitentna oblika MS,
• Zdravljenje z imunomodulatornimi zdravili,
• Starost 18-60 let in
• EDSS (angl. Expanded Disability Status Scale) manj kot 5.

E.4

Principal exclusion criteria

• Use of vitamin D supplements in the past 3 months
• Pregnancy, planing pregnancy or nursing
• Relapse of disease and corticosteroide use in past month
• Active inflammmation at the start of the study (flu, cystitis etc.)
• Renal disease
• Elevated levels od calcium or parathormone
• Hypersensitivity to vitamin D prepartions
• Switching of immunomodulatory drug in past 3 months
• Other autoimmune disease
• History of hyperparathyroidism, liver disease, tuberculosis, sarcoidosis or kidney stones

• jemanje nadomestkov vitamina D manj kot tri mesece pred začetkom raziskave,
• nosečnost, načrtovanje nosečnosti ali dojenje,
• zagon bolezni in zdravljenje s kortikosteroidi v zadnjem mesecu dni,
• povišani vnetni pokazatelji ob začetku raziskave (prehladi, vnetja mehurja itd.),
• ledvična okvara,
• povišane vrednosti kalcija ali parathormona v serumu,
• znana preobčutljivost na učinkovino,
• menjava imunomodulatorne terapije v zadnjih 3 mesecih,
• pridružene avtoimune bolezni in
• anamneza hiperparatiroidizma, jetrnih bolezni, tuberkuloze, sarkoidoze ali ledvičnih kamnov v preteklosti.

E.5 End points

E.5.1

Primary end point(s)

Change in vitamin D level in serum after supplementation.

Sprememba nivoja vitamina D po nadomeščanju.

E.5.1.1

Timepoint(s) of evaluation of this end point

4 months (December 2017-April 2018)

4 meseci (december 2017-april 2018)

E.5.2

Secondary end point(s)

Change in gene expression of products of Th17 cells and their co-factors
Change in miR-155 expression before and after vitamin D supplementation.
Genotypization of selected SNP's and try to determine pharmacogenomic linkage with effect of vitamin D supplementation

Sprememba v izražanju genov produktov Th17 celic in njihovih kofaktorjev
Sprememba v izražanju miR-155 po nadomeščanju vitamina D
Genotipizacija izbranih SNP-jev in ugotavljanje farmakogenomske povezave z učinkom nadomeščanja

E.5.2.1

Timepoint(s) of evaluation of this end point

4 months (December 2017-April 2018)

4 meseci december 2017-april 2018)

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

Information not present in EudraCT

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

The study will end 4 months after starting supplementation

Raziskava se zaključi po 4 mesecih od začetka nadomeščanja

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:

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

F.3.3.2

Women of child-bearing potential using contraception

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.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)

None.

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

2017-12-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-28

P. End of Trial
P.	End of Trial Status	Ongoing

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