Clinical Trials Register

Summary
EudraCT Number:	2019-000069-19
Sponsor's Protocol Code Number:	MS700568_0026
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-06-12
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2019-000069-19

A.3

Full title of the trial

Evaluating the Long-Term Outcomes and Durability of Effect Following Treatment with Cladribine Tablets for Multiple Sclerosis: An Exploratory Phase IV Ambispective Study of Patients Who Previously Participated in the CLARITY/CLARITY-EXT and ORACLE MS Clinical Trials

A.3.1

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

beoordelen van de resultaten op de lange termijn en duurzaamheid van
het effect na behandeling met cladribine-tabletten voor multiple sclerose: een verkennende
ambispectieve fase IV-studie naar patiënten die eerder hebben deelgenomen aan de klinische
studies CLARITY/CLARITY-EXT en ORACLE MS

A.3.2

Name or abbreviated title of the trial where available

CLASSIC-MS

A.4.1

Sponsor's protocol code number

MS700568_0026

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 Str. 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	D-64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496151 725200
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 tablets
D.3.2	Product code	Not applicable
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.3.11 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

MS is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) and is the most common cause of serious neurological disability in young adults (Przybek, 2015). With no definite cause established, MS has been hypothesised to result from a complex interaction between individual genetic susceptibility and environmental factors that act as triggers of a self-sustained auto-immune response (Noseworthy, 2000).

E.1.1.1

Medical condition in easily understood language

MS is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) and is the most common cause of serious neurological disability in young adults

Multiple Sclerose

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	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10029205
E.1.2	Term	Nervous system disorders
E.1.2	System Organ Class	10029205 - Nervous system disorders

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 evaluate long-term mobility after treatment with an investigational medicinal product (IMP; Cladribine
Tablets or placebo) as part of the Phase III ORACLE MS and CLARITY/CLARITY-EXT clinical trials.

de gegevens zullen retrospectief en prospectief worden verzameld om de resultaten op de lange termijn, duurzaamheid van het effect en daadwerkelijke behandelingspatronen na behandeling met cladribine-tabletten of placebo te beoordelen bij patiënten met MS die deelnamen aan de bronstudies. Alle doelstellingen van deze studie zijn verkennend en bedoeld voor het genereren van hypotheses.

E.2.2

Secondary objectives of the trial

1. To assess the long-term disability status after treatment with IMP as part of the Phase III ORACLE MS and CLARITY/CLARITY-EXT clinical trials for the CLARITY/CLARITY-EXT and ORACLE MS populations.
2. To evaluate differences in clinical characteristics between long-term responders and study participants
requiring alternate therapies following treatment with IMP for the CLARITY/CLARITY-EXT and ORACLE
MS populations.
MRI Sub-Study:
3. To evaluate differences in magnetic resonance imaging (MRI) characteristics between long-term responders and study participants requiring alternate therapies following treatment with IMP for the
CLARITY/CLARITY-EXT and ORACLE MS populations.

De proportie studiedeelnemers met een 3 maanden aanhoudende EDSS van 6,0 of hoger in het jaar voorafgaand aan de registratie (d.w.z. ambulante beperking in overeenstemming met EDSS bij ten minste 2 bezoeken aan de kliniek met niet minder dan 3 maanden ertussen) zoals bepaald door EDSS-documentatie of overeenkomende klinische beschrijving in medische dossiers voor de CLARITY/CLARITY-EXT- en ORACLE MS-populaties.

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

MRI Sub-Study as integral part of the protocol v1.0 28.Jan.2019

E.3

Principal inclusion criteria

For Main Study and MRI Sub-Study:
1. Patients with MS randomised in CLARITY/CLARITY-EXT clinical trial(s) who have received ≥ 1 course of IMP (Cladribine Tablets or placebo).
or
Patients with their FCDE randomised in ORACLE MS clinical trial who have received
≥ 1 course of IMP (Cladribine Tablets or placebo).
2. Patients can give signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and this protocol.

E.4

Principal exclusion criteria

Main study:
Any condition, including any uncontrolled disease state other than MS, that in the Investigator’s
opinion, constitutes an inappropriate risk or a contraindication for participation in the study or that
could interfere with the study objectives, conduct, or evaluation.
MRI-Substudy:
a. Female study participants who are pregnant
b. Patient is taking Cladribine Tablets as part of another study at the time of the start of
this study (i.e. patients participating in a clinical trial or observational study but do not
receive Cladribine Tablets as part of these studies are allowed to participate in the substudy).

E.5 End points

E.5.1

Primary end point(s)

Proportion of study participants using a wheelchair (defined as unable to walk beyond approximately 5 meters even with aid, essentially restricted to wheelchair; wheels self in standard wheelchair and
transfers alone; up and about in wheelchair some 12 hours a day) the majority of the time in the 3 month prior to Study Visit 1 for the CLARITY/CLARITY-EXT and ORACLE MS populations, determined via:
• Expanded Disability Status Scale (EDSS)
score of 7.0 or higher (if available), or
• Alternative clinical description data in medical records.

E.5.1.1

Timepoint(s) of evaluation of this end point

Study visit 1

E.5.2

Secondary end point(s)

1. Proportion of study participants with 3-month sustained EDSS of 6.0 or higher in the last year prior to enrolment (i.e.ambulatory disability consistent with EDSS on at least 2 clinic visits no less than 3 months apart) as determined by EDSS documentation or corresponding clinical description in medical records for the CLARITY/CLARITY-EXT and ORACLE MS populations
2. Clinical characteristics of long-term responders (defined as study participants who did not demonstrate any evidence of disease reactivation based on Investigator assessment of clinical and imaging outcomes until Year 4 or later following their last dose of IMP and who did not receive disease modifying treatment until Year 4 or later following their last dose of IMP) compared to those of other study participants who started on alternate therapy less than 4 years following their last dose of IMP for the CLARITY/CLARITY-EXT and ORACLE MS populations.
MRI Sub-Study:
3. MRI characteristicsc at Study Visit 2 of longterm responders (defined as study participants who did not demonstrate any evidence of disease reactivation based on Investigator assessment of clinical and
imaging outcomes until Year 4 or later following their last dose of IMP and who did not receive disease modifying treatment until Year 4 or later following their last dose of IMP) compared to those of other study participants who started on alternate therapy less than 4 years following their last dose of IMP for the CLARITY/CLARITY-EXT and ORACLE MS populations.

E.5.2.1

Timepoint(s) of evaluation of this end point

ad 1. Study Visit 1
ad 2. Study Visit 1
ad 3. Study visit 2

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

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

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

Yes

E.8.1.7.1

Other trial design description

Ambispective; data from patients participating to past trials. No IMP treatment during this study

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

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

Austria

Belgium

Bulgaria

Canada

Croatia

Czech Republic

Estonia

Finland

France

Georgia

Germany

Greece

Italy

Korea, Republic of

Latvia

Lebanon

Lithuania

Morocco

Norway

Poland

Portugal

Romania

Russian Federation

Serbia

Spain

Sweden

Switzerland

Tunisia

Ukraine

United Kingdom

United States

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:

920

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 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 2019-06-12.

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients who cannot participate or complete the schedule of activities due to cognitive impairment or relapsing episode will be given the opportunity to participate by their proxy/caregiver/legal representative providing consent on their behalf.

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

550

F.4.2.2

In the whole clinical trial

1000

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)

Not applicable

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

2019-06-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-02-27

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