Clinical Trials Register

Summary
EudraCT Number:	2017-002631-42
Sponsor's Protocol Code Number:	MS700568_0022
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:	2018-01-30
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

Czechia - SUKL

A.2

EudraCT number

2017-002631-42

A.3

Full title of the trial

A 2-year prospective study to evaluate the onset of action of Mavenclad® in subjects with highly active relapsing multiple sclerosis

2letá prospektivní studie ke zhodnocení nástupu účinku přípravku Mavenclad® u pacientů s vysoce aktivní relabující roztroušenou sklerózou

A.3.1

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

A Clinical Research Study for People with Relapsing Multiple Sclerosis

A.4.1

Sponsor's protocol code number

MS700568_0022

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	Merck KGaA
B.1.3.4	Country	Germany
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	Merck KGaA
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck KGaA
B.5.2	Functional name of contact point	Communication Center Merck KGaA
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Strasse 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 6151 72 5200
B.5.5	Fax number	+496151722000
B.5.6	E-mail	service@merckgroup.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	Mavenclad®
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Europe B.V.
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	Cladribine
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	CLADRIBINE
D.3.9.1	CAS number	4291-63-8
D.3.9.2	Current sponsor code	EMD280922
D.3.9.3	Other descriptive name	2-chloro-2’-deoxyadenosine (2-CdA)
D.3.9.4	EV Substance Code	SUB06635MIG
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	10
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 multiple sclerosis

E.1.1.1

Medical condition in easily understood language

Relapsing multiple sclerosis

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	PT
E.1.2	Classification code	10028245
E.1.2	Term	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 determine the onset of action of Mavenclad®in subjects with highly active relapsing multiple sclerosis (RMS).

E.2.2

Secondary objectives of the trial

To assess the effect of Mavenclad® on different immune system composites in particular cell subtypes count and repopulation

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

1- OCT Substudy : This sub-study explores the concept of using OCT as a structural biomarker of disease development in MS patients. The goal of this exploratory sub-study is to investigate the axonal degeneration in subjects enrolled
into the trial, by measuring the RNFL thickness with OCT.
The three objectives of this exploratory sub-study are:
-To describe the axonal degeneration at 12 and 24 months compared to baseline
-To describe the correlation of axonal degeneration with ‘traditional’ MS related assessments (e.g. MRI, EDSS…)
-To describe changes in RNFL thinning over time

2- DTI and fMRI Sub-study: This sub-study explores the concept of using DTI and fMRI as a structural biomarker of disease
that are specific for brain tissue injury and repair.
The goal of this exploratory sub-study is to investigate the brain structural and functional changes in subjects enrolled into the trial, by measuring DTI and fMRI over time.
The three objectives of this exploratory sub-study are:
-To describe the changes in DTI and fMRI at 12 and 24 months compared to baseline
-To describe the correlation of DTI and fMRI with ‘traditional’ MS related assessments (e.g. MRI, EDSS…)
- To describe changes in DTI and fMRI over time

3 CSF Biomarker Sub-study: Validated biomarkers will help to define an optimal cladribine treatment response in MS and thus be of considerable value for taking treatment decisions and ensuring continued benefit from cladribine therapy. The candidate biomarkers have been selected on basis of evidences from literature.
The goal of this exploratory sub-study is to investigate the surrogate marker in subjects enrolled into the
trial, by measuring CSF biomarkers over time.
The objectives of this exploratory sub-study are:
-To describe the changes in CSF biomarkers at 12 and 24 months compared to baseline
- To describe the correlation of biomarkers with ‘traditional’ MS related assessments (e.g. MRI, EDSS…)
- To describe changes in biomarker over time

4- Blood Biomarker Sub-study
The goal of this exploratory sub-study is to investigate the surrogate marker in patients enrolled into the trial, by measuring blood biomarkers over time.
The objectives of this exploratory sub-study are:
-To describe changes in biomarker over time
-To describe the correlation of biomarkers with ‘traditional’ MS related assessments (e.g. MRI, EDSS)

E.3

Principal inclusion criteria

•Male or female subjects ≥ 18 years old
•Highly active RMS as defined by:
-One relapse in the previous year and at least 1 T1 Gd+ lesion or 9 or more T2 lesions, while on therapy with other disease modifying drugs (DMDs)
-Two or more relapses in the previous year, whether on DMD treatment or not
•EDSS score ≤5.0

E.4

Principal exclusion criteria

•Previous exposure to drugs such as fingolimod, natalizumab, alemtuzumab, mitoxantrone and ocrelizumab
•Positive test for hepatitis C or positive tests for hepatitis B infection: either hepatitis B surface antigen (HBsAg) positive, or positive hepatitis B core antibody (total anti HBcAb) confirmed by a positive viral polymerase chain reaction (PCR)
•Current or previous history of immune deficiency disorders including a positive human immunodeficiency virus (HIV) result
•Currently receiving immunosuppressive or myelosuppressive therapy with, e.g., monoclonal antibodies, methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic use of corticosteroids
•History of tuberculosis , presence of active tuberculosis, or latent tuberculosis
- Presence of signs of PML detected by MRI, clinical and /or biomarker evaluations
•Acive malignancy
• lymphocyte count not within normal limits of the local hospital lab before initiation of first treatment course

E.5 End points

E.5.1

Primary end point(s)

•Differences in the counts of combined unique active (CUA) MRI lesions
lesions during the first 6 months (i.e. during periods months 1-6, 2-6, 3-
6) compared to baseline (i.e. the period screening to baseline)

E.5.1.1

Timepoint(s) of evaluation of this end point

•At the end of 6 months compared to baseline

E.5.2

Secondary end point(s)

•Characterization of immune cell subsets count

E.5.2.1

Timepoint(s) of evaluation of this end point

•At the end of 3, 6, 12, 15, 18 and 24 months compared to baseline

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)

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.8.2.4

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

Canada

Israel

Austria

Belgium

Denmark

Finland

France

Germany

Ireland

Italy

Netherlands

Norway

Spain

Sweden

Switzerland

United Kingdom

Czechia

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 end of the trial is defined as the last subject’s End of Trial visit.

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:

260

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

250

F.4.2.2

In the whole clinical trial

265

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)

Upon completion of study, subjects will be offered the opportunity of enrolling into an Extension study for a further 2 years (i.e., until 4 years from first treatment year course). A separate protocol will be followed for the Extension study.
Patients who will not roll over to the extension study will return to their standard of care treatment.

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

2018-03-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-10-08

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