Clinical Trials Register

Summary
EudraCT Number:	2007-000381-20
Sponsor's Protocol Code Number:	27820
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:	2008-02-28
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

Germany - BfArM

A.2

EudraCT number

2007-000381-20

A.3

Full title of the trial

A Phase IIIb, Double-Blind, Placebo-Controlled, Multicenter, Parallel Group, Extension Trial to Evaluate the Safety and Tolerability of Oral Cladribine in Subjects with Relapsing-Remitting Multiple Sclerosis Who Have Completed Trial 25643 (CLARITY).

A.3.1

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

CLARITY Extension Study

A.3.2

Name or abbreviated title of the trial where available

CLARITY EXTENSION

A.4.1

Sponsor's protocol code number

27820

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00641537

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 Serono S.A. - Geneva
B.1.3.4	Country	Switzerland
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 Serono S.A. - Geneva
B.4.2	Country	Switzerland
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 5151 72 5200
B.5.5	Fax number	+ 49 5151 72 2000
B.5.6	E-mail	service@merck.de

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	No
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.3.2	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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLADRIBINE
D.3.9.1	CAS number	4291638
D.3.9.2	Current sponsor code	EMD280922
D.3.9.3	Other descriptive name	2-chloro-2’-deoxyadenosine (2-CdA)
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

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 (RRMS)

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
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

Safety Objectives:
• Evaluate the safety of extended treatment with oral cladribine when administered according to a fixed annual dosing schedule to subjects who completed Trial 25643 (CLARITY)
• To assess the safety of cladribine with an emphasis on cardiac repolarization as measured by changes in QT interval (in a subset of patients also partipating in the PK sampling and analysis).

E.2.2

Secondary objectives of the trial

• Explore the long-term benefit of treatment with oral cladribine vs. placebo
• Explore the relationship between oral cladribine treatments and various immunologic parameters, MRI measures of disease activity, clinical relapses and disease progression in subjects previously randomised in Trial 25643
• Determine the benefit of continued oral cladribine treatment on health-related quality of life and economic outcome measures
• Explore the association between genetic variants, clinical efficacy, MRI endpoints and groups of subject with adverse events (grade 3 and 4 toxicity)
• Explore the effect of oral cladribine on gene expression profiles
• Assess population pharmacokinetics

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

° Were randomised in Trial 25643 and satisfy one of the following:
- Completed their randomised treatment course and scheduled visits for the full 96 weeks (a)(b); or
- Did not complete the randomized treatment course in Trial 25643, but who elected to receive rescue treatment with Rebif or another beta-interferon or glatiramer acetate, and who completed scheduled clinic visits for the full 96 weeks; or
- Did not complete the randomised treatment course in Trial 25643, declined rescue with Rebif or another beta-interferon or glatiramer acetate, and still completed scheduled clinic visits for the full 96 weeks; or
- Did not complete the randomised treatment course in Trial 25643, were not eligible for rescue option with Rebif, and still completed scheduled clinic visits for the full 96 weeks.

° Be male or female and between 18 and 65 years of age (inclusive, at time of informed consent prior to entry into Trial 25643)

° Have no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test or chest X-ray;
NOTE: For subjects with medical history or LTBI ot TB, please refer to Appendices L, M, N. Subjects who should be excluded from blinded medication could be proposed to be followed for safety according to the same scheduled visits

° All of the following laboratory hematologic parameters must be normal (as defined below, inclusively) within 28 days of first dosing of blinded study medication at SD1:
- Hemoglobin = 11.6 – 16.2 G/DL
- Leukocyctes (total white blood cells [WBC]) = 4.1 – 12.3 x 10E3/UL
- Absolute lymphocytes = 1.02 – 3.36 x 10E3/UL
- Absolute neutrophil count (ANC) = 2.03 – 8.36 x10E3/UL
- Platelet count = 140-450 x 10E3/UL
NOTE: For subjects with abnormal laboratory hematological parameters, please refer to section 6.2.1 for retesting guidelines. Subjects who should be excluded from blinded medication during the current yearly dosing could be proposed to be followed for safety according to the same scheduled visits.

° Female subjects must be neither pregnant nor breast-feeding and must lack child-bearing potential, as defined by either:
- Be post-menopausal or surgically sterilized; or
- Using a highly effective method of contraception throughout the entire duration of the study and for 6 months (6 menstrual cycles) following completion of the last dose of study medication. A highly effective method of contraception is defined as those which result in a low failure rate (i.e. less that 1% per year) when used consistently and correctly such as implants, injectables, comined with oral contraceptives, IUSs, sexual abstinence or vasectomised partner.
- Treatment of pregnant and nursing women with cladribine is prohibited.

° If male, he must be willing to use contraception to avoid pregnancies throughout the entire duration of the study and for 90 days following the last dose of study medication or following early termination or early withdrawal.

° Voluntarily provide written informed consent, and for USA sites only, a subject authorization under Health Insurance Portability and Accountability Act (HIPAA)

° Absence of history or available abnormal laboratory results indicative of any significant or unstable cardiac, endocrinologic, hematologic (other than abnormal laboratory results consistent with prior exposure to oral cladribine), hepatic, immunologic (other than MS), metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric (including major depression), and/or other major disease,
that would preclude the administration of oral cladribine over a 24-month course of treatment
° Absence of moderate to severe renal impairment

E.4

Principal exclusion criteria

° Have prior or current malignancy other than medically documented complete excision of basal cell skin cancer no less than 5 years prior to Screening;

° Have a history of chronic or clinically significant hematological abnormalities;

° Has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase > 2.5 times the upper limit of the normal values;

° Suffers from major medical illness such as cardiac, endocrinologic, hepatic, immunologic (other than MS), metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine.

° Suffers from major psychiatric illness (including history of, or current, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol;

° History of active or chronic infectious disease or any disease which compromises immune function (e.g. HIV+, HTLV-1, Lyme disease);

° Have an allergy or hypersensitivity to gadolinium, to cladribine or any of its excipients, or IFN-b or any of its excipient(s);

° Subject has any renal condition that would preclude to the administration of gadolinium (e.g.acute or chronic severe renal insufficiency (GFR <30 mL/min/1.73 m2)

° Have a positive stool heme-occult test at Pre-Study Evaluation (PSE);
NOTE: For subjects with positive heme-occult test, please refer to section 6.4.6 for retesting guidelines. Subjects who should be excluded from blinded medication during the current yearly dosing could be proposed to be followed for safety according to the same scheduled visits.

° Subject has a history of seizures not adequately controlled by treatment.

° Concurrent enrolment in any other investigational drug trial with the exception of any Sponsor sub-trial of this protocol that is approved by the Medical Director

° Any other reason(s) that, in the opinion of the Investigator and/or the Sponsor, would indicate that the subject is unsuitable for inclusion in this extension trial

° Treatment with a beta-interferon or glatiramer acetate less than 3 months prior to Study Day 1 during any gap between completion of CLARITY Trial 25643 and CLARITY Extension Trial 27820

° Use of mitoxantrone, total lymphoid irradiation, myelosuppressive therapy, campath-1h, cyclophosphamide, azathioprine, methotrexate or natalizumab at anytime during and since Study 25643

NOTE: For subjects who had to delay entry into the CLARITY Extension study or the 24-Week Supplemental Follow-up portion whereby there was a gap interval of varying duration, who subsequently, during the gap interval were treated with a DMD or Rebif should discontinue the DMD or Rebif for a period of at least 3 months prior to Study Day 1. For those subjects who are unable or are unwilling to discontinue their DMD, they may not be re- randomized to receive study medication. These subjects are encouraged to enter the study but will be followed for safety only.

NOTE: For subjects who had to delay entry into the CLARITY Extension study or the 24-Week Supplemental Follow-up portion, whereby there was a gap interval of varying duration, who subsequently during the gap interval were treated with a prohibited medication (See exclusion criteria section 5.2.2.) will not be eligible for the enrollment in the future open-label study. These subjects are encouraged to enter the 24-Week Supplemental Follow-up, but will be followed for safety only.

° Use of cytokine or anti-cytokine therapy, intravenous immunoglobulin (IVIG) or plasmapheresis since their completion of Trial 25643

° Treatment with oral or systemic corticosteroids or adrenocorticotropic hormone within 28 days before Study Day 1

E.5 End points

E.5.1

Primary end point(s)

Safety endpoints:
° Proportion of subjects with at least one grade 4 CTCAE toxicity on the following parameters of hematologic and hepatic function: absolute lymphocyte count (ALC),
hemoglobin level, white blood cell (WBC) count, absolute neutrophil count (ANC), platelets, alanine transaminase (ALT), aspartate transaminase (AST) and bilirubin
° Proportion of subjects with grades 3 or 4 adverse events (AEs) for hematologic and hepatic indices
° Mean change in absolute lymphocyte count, hemoglobin level, WBC, ANC, platelets, ALT, AST, and bilirubin
° Incidence of all treatment emergent AEs and SAEs
° Proportion of subjects developing infections, infection-related AEs and malignancies
° Time to first grade 3 and 4 hematological toxicity or liver toxicity
° Median and mean time to recovery from hemtological and liver toxicity
° Median and mean time to nadir of absolute lymphocyte count and mean time to recovery to normal values
° Mean change in QTc interval from baseline

Clinical Efficacy Endpoints:
° Proportion of subjects relapse free (qualifying and/or non-qualifying)
° Disability progression. The following three progression endpoints will be used:
o Time to confirmed EDSS progression, confirmed after 3 months
o Time to confirmed EDSS progression, confirmed after 6 months
o Confirmed progressions (sustained over a period of at least 3 months) assessed at annual intervals
° Time to treatment start with rescue medication
° Annualized relapse rate (qualifying and/or non-qualifying)
° Time to first relapse (qualifying and/or non-qulaifying)
° Time to second relapse (qualifying and/or non-qualifying)

MRI endpoints:
° Number of new T1 gadolinium-enhanced lesions
° Number of active T2 lesions
° Number of combined unique (CU) lesions defined as 1) new T1 gadoliniumenhancing, or 2) new T2 non-enhancing or enlarging lesions, or 3) both, without double-counting
° Total T2 lesion volume (the proton density/T2-weighted (T2) burden of disease (BOD))
° Proportion of T1 gadolinium-enhanced lesions assessed at Baseline of Trial 25643
transformed in T1 hypointense lesions (black holes)
° Percent brain volume changes
° Proportion of subjects with no new T1 gadolinium-enhanced lesions
° Proportion of subjects with no active T2 lesions
° Proportion of subjects with no combined unique lesions
° Number of new T1 hypointense lesions
° Mean change in volume of T1 hypointense lesions

E.5.1.1

Timepoint(s) of evaluation of this end point

96 weeks and 120 weeks

E.5.2

Secondary end point(s)

Not Applicable

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

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)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

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

Information not present in EudraCT

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

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

Brazil

Bulgaria

Canada

Croatia

Czech Republic

Denmark

Estonia

Finland

France

Germany

Greece

Italy

Latvia

Lebanon

Lithuania

Morocco

Netherlands

Poland

Portugal

Russian Federation

Saudi Arabia

Serbia

Switzerland

Turkey

Ukraine

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Information not present in EudraCT

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

700

F.4.2.2

In the whole clinical trial

1100

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)

Following completion of the study, the treating physician should discuss available treatment options
with the subject. Given cladribine’s mechanism of action (lymphocytotoxicity), caution must be
exercised regarding choice of post-study treatment. Any treatment that has a different mechanism
of action from that of cladribine but which is myelosuppressive must be used with caution in order
to minimize potential toxicity.
Please refer to the protocol section 6.2.6 for more information.

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

2008-02-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-03-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-02-16

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