Clinical Trials Register

Summary
EudraCT Number:	2020-003995-42
Sponsor's Protocol Code Number:	MS700568_0157
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-10-29
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

Germany - BfArM

A.2

EudraCT number

2020-003995-42

A.3

Full title of the trial

A 2-year extension study to evaluate long-term effectiveness of Mavenclad® in participants who have completed Trial MS700568_0022 (MAGNIFY MS)

Zweijährige Anschlussstudie zur Bewertung der langfristigen Wirksamkeit von Mavenclad® bei Personen, die die Studie MS700568_0022 (MAGNIFY MS) abgeschlossen haben

A.3.1

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

Extension to the MAGNIFY MS trial on Mavenclad®

Anschlussstudie zur Studie MAGNIFY MS zu Mavenclad®

A.3.2

Name or abbreviated title of the trial where available

Magnify MS Extension

A.4.1

Sponsor's protocol code number

MS700568_0157

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 Healthcare 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 Healthcare 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 Healthcare 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	49615172 5200
B.5.5	Fax number	49615172 2000
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

Highly-active relapsing multiple sclerosis

Hochaktive schubförmige Multiple Sklerose (RMS)

E.1.1.1

Medical condition in easily understood language

multiple sclerosis (MS)

Multiple Sklerose (MS)

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.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10080700
E.1.2	Term	Relapsing 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 the long-term disease activity during Year 3 and 4 after initial dose of cladribine tablets

Bewertung der langfristigen Krankheitsaktivität in Jahr 3 und 4 nach der Erstbehandlung mit Cladribin-Tabletten

E.2.2

Secondary objectives of the trial

1. To further explore the long-term treatment effect of cladribine tablets;
2. To evaluate the long-term safety of cladribine tablets

1. Weitere Untersuchung der langfristigen Auswirkungen einer Behandlung mit Cladribin-Tabletten;
2. Bewertung der langfristigen Sicherheit von Cladribin-Tabletten

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. Blood biomarker sub-study (appendix 3 of main study protocol), v. 1.0 , 20 Aug 2020
Objectives:
• To describe changes in biomarkers over time during the extension study period (Year 3 and 4 since the initial dose of cladribine tablets)
• To describe changes in biomarkers in Year 1, 2, 3, and 4 since the initial dose of cladribine tablets
• To describe the correlation of biomarkers with “traditional” MS related assessments (e.g. MRI and EDSS).

2. CSF Biomarker sub-study (appendix 4 of main study protocol), v. 1.0, 20 Aug 2020
Objectives:
• To describe the changes in CSF biomarkers at Year 3 and year 4 after treatment with cladribine tablets, compared to the extension study’s baseline
• To describe the changes in CSF biomarkers at Year 1, 2, 3, and 4 after treatment with cladribine tablets, compared to the parent study baseline
• To describe the correlation of biomarkers with ‘traditional’ MS related assessments (e.g. MRI and EDSS)
• To describe changes in biomarker over time

3. COVID-19 sub-study (appendix 5 of main study protocol) v. 1.0, 20 Aug 2020
Objectives:
• To describe the changes in antibody titers against COVID-19
• To describe the changes in immune cell subtypes in those who show positive serology test
• To describe the MS disease outcome and study endpoints collected in those who show positive serology test
• To describe changes in antibody titers against COVID-19 vaccine (if available and administered, as per standard of care)
• To describe changes in antibody titers against any vaccine (if available and administered, as per standard of care)

E.3

Principal inclusion criteria

1. Participants of the MAGNIFY MS trial who received at least a single dose of cladribine tablets during the MAGNIFY MS trial and data on MRI is available/acquired from at least parent study Month 18 or Month 24 visit and EDSS and relapse from parent study Month 24 visit.
2. Capable of giving signed informed consent, as indicated in Appendix 2, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol.

E.4

Principal exclusion criteria

1. Participant is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.
2. Participation in other studies/trials.

E.5 End points

E.5.1

Primary end point(s)

Proportion of participants with No Evidence of Disease Activity (three parameter [NEDA-3]) during Year 3 and 4 after the initial dose of cladribine tablets.

Anteil der Teilnehmer ohne messbare Krankheitsaktivität (NEDA-3) in Jahr 3 und 4 nach der Erstbehandlung mit Cladribin-Tabletten.

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 1: 12 months (+/- 30 days) after parent study last visit
Visit 2: 24 months (+/- 30 days) after parent study last visit

Besuchstermin 1: 12 Monate (+/- 30 Tage) nach dem letzten Termin der Hauptstudie
Besuchstermin 2: 24 Monate (+/- 30 Tage) nach dem letzten Termin der Hauptstudie

E.5.2

Secondary end point(s)

• Proportion of participants with NEDA-3 during Year 3 after the initial dose of cladribine tablets
• Proportion of participants with NEDA-3 during Year 4 after the initial dose of cladribine tablets
• Proportion of participants with NEDA-3 after the onset of action of cladribine treatment during the parent study until the end of Year 3 after initial dose of cladribine tablets
• Proportion of participants with NEDA-3 after onset of action of cladribine treatment during the parent study until the end of Year 4 after the initial dose of cladribine tablets
• Proportion of participants remaining NEDA-3 during Year 3 or 4 after the initial dose of cladribine tablets among those with NEDA-3 during Year 1 or 2 after the initial dose of cladribine tablets
• Time to first disease activity, deﬁned as time to ﬁrst occurrence of either qualifying relapse, or confirmed disability progression (CDP), or new or enlarging T2-hyperintense lesions, or new T1 gadolinium enhancing (Gd+) lesions, during Year 3 and 4 after the initial dose of cladribine tablets
• Time to first disease activity, deﬁned as time to first occurrence of either qualifying relapse, or CDP, or new or enlarging T2-hyperintense lesions, or new T1 Gd+ lesions, over 4 years after the initial dose of cladribine (i.e., between the initial dose of cladribine tablets and end of the extension study)
• Time from the initial dose of cladribine tablets to
- first new or enlarging T2 lesion
- first new T1 Gd+ lesion
- first CDP, as measured by Expanded Disability Status Scale (EDSS)
- first qualifying relapse
- second qualifying relapse
- treatment start with other disease modifying drugs (DMDs)
• Time from extension study Baseline to
- first new or enlarging T2 lesion
- first new T1 Gd+ lesion
- first CDP, as measured by EDSS
- first qualifying relapse
- second qualifying relapse
- treatment start with other DMDs

• Anteil der Teilnehmer ohne messbare Krankheitsaktivität (NEDA-3) in Jahr 3 nach der Erstbehandlung mit Cladribin-Tabletten
• Anteil der Teilnehmer ohne messbare Krankheitsaktivität (NEDA-3) in Jahr 4 nach der Erstbehandlung mit Cladribin-Tabletten
• Anteil der Teilnehmer ohne messbare Krankheitsaktivität (NEDA-3) nach Wirkungseintritt von Cladribin während der Hauptstudie bis zum Ende von Jahr 3 nach der Erstbehandlung mit Cladribin-Tabletten
• Anteil der Teilnehmer ohne messbare Krankheitsaktivität (NEDA-3) nach Wirkungseintritt von Cladribin während der Hauptstudie bis zum Ende von Jahr 4 nach der Erstbehandlung mit Cladribin-Tabletten
• Anteil der Teilnehmer, die in Jahr 1 oder 2 nach der Erstbehandlung mit Cladribin-Tabletten keine messbare Krankheitsaktivität (NEDA-3) aufwiesen und auch noch in Jahr 3 oder 4 nach der Erstbehandlung in die NEDA-3-Kategorie fallen
• Zeitraum bis zur ersten Krankheitsaktivität, definiert als Zeitraum bis zum ersten Auftreten eines der Definition entsprechenden Rückfalls oder des bestätigten Fortschreitens der Behinderung (CDP) oder neuer oder sich vergrößernder hyperintenser T2-Läsionen oder neuer Gadolinium anreichernder (Gd+) T1-Läsionen in Jahr 3 und 4 nach der Erstbehandlung mit Cladribin-Tabletten
• Zeitraum bis zur ersten Krankheitsaktivität, definiert als Zeitraum bis zum ersten Auftreten eines der Definition entsprechenden Rückfalls oder CDP oder neuer oder sich vergrößernder hyperintenser T2-Läsionen oder neuer Gd+ T1-Läsionen in den vier Jahren nach der Erstbehandlung mit Cladribin-Tabletten (also zwischen der ersten Einnahme und dem Ende der Anschlussstudie)
• Zeitraum zwischen der ersten Einnahme von Cladribin und
• der ersten neuen oder sich vergrößernden T2-Läsion
• der ersten neuen Gd+ T1-Läsion
• dem ersten bestätigten Fortschreiten der Behinderung CPD, gemessen anhand der EDSS-Ergebnisse
• dem ersten Auftreten eines der Definition entsprechenden Rückfalls
• dem zweiten Auftreten eines der Definition entsprechenden Rückfalls
• dem Beginn der Behandlung mit weiteren krankheitsmodifizierenden Arzneimitteln (DMDs)
• Zeitraum zwischen dem Beginn der Anschlussstudie und
• der ersten neuen oder sich vergrößernden T2-Läsion
• der ersten G+ T1-Läsion
• dem ersten bestätigten Fortschreiten der Behinderung CPD, gemessen anhand der EDSS-Ergebnisse
• dem ersten Auftreten eines der Definition entsprechenden Rückfalls
• dem zweiten Auftreten eines der Definition entsprechenden Rückfalls
• dem Beginn der Behandlung mit weiteren DMDs

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit 1: 12 months (+/- 30 days) after parent study last visit
Visit 2: 24 months (+/- 30 days) after parent study last visit

Besuchstermin 1: 12 Monate (+/- 30 Tage) nach dem letzten Termin der Hauptstudie
Besuchstermin 2: 24 Monate (+/- 30 Tage) nach dem letzten Termin der Hauptstudie

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

Phase IV extension; 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

Canada

Israel

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

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:

256

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 2020-10-29.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

Yes

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

214

F.4.2.2

In the whole clinical trial

256

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

Nicht zutreffend

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

2020-11-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-09-21

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