Clinical Trials Register

Summary
EudraCT Number:	2012-000411-91
Sponsor's Protocol Code Number:	NKZellen-Version1.0
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:	2012-12-04
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

2012-000411-91

A.3

Full title of the trial

Monitoring natural killer cells in multiple sclerosis patients treated with fingolimod: a monocentric, prospective, one year, baseline-to-treatment, open-label, single group pilot trial

Untersuchung der natürlichen Killer (NK-) Zellen in Patienten
mit Multipler Sklerose unter Fingolimod-Behandlung: Eine monozentrische, prospektive, offene, einarmige Studie

A.3.1

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

Monitoring natural killer cells in multiple sclerosis patients treated with fingolimod

Untersuchung der natürlichen Killer (NK-) Zellen in Patienten
mit Multipler Sklerose unter Fingolimod-Behandlung

A.3.2

Name or abbreviated title of the trial where available

NKZellen-Version1.0

A.4.1

Sponsor's protocol code number

NKZellen-Version1.0

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	Charité - Universitätsmedizin Berlin
B.1.3.4	Country	Germany
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	Charité - Universitätsmedizin Berlin
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Novartis
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	Charité - Universitätsmedizin Berlin
B.5.2	Functional name of contact point	NeuroCure
B.5.3	Address:
B.5.3.1	Street Address	Charitéplatz 1
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	10117
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4930450 660162
B.5.5	Fax number	+4930450 539921
B.5.6	E-mail	jan-markus.doerr@charite.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	Yes
D.2.1.1.1	Trade name	Gilenya®
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Gilenya®
D.3.2	Product code	Gilenya®
D.3.4	Pharmaceutical form	Capsule, hard
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	Fingolimod
D.3.9.1	CAS number	162359-55-9
D.3.9.2	Current sponsor code	FINGOLIMOD
D.3.9.3	Other descriptive name	FINGOLIMOD
D.3.9.4	EV Substance Code	SUB31908
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	0,5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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

E.1.1.1

Medical condition in easily understood language

multiple sclerosis

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

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 investigate longitudinally (baseline vs. treatment) the effects of fingolimod on NK cell maturation/differentiation

We hypothesize that fingolimod targets certain NK cell subsets, which could cause a reduction of the ratio of immature NK cells / total NK cells and may account for therapeutic benefit and, thus, for treatment response discrimination in patients with MS.

E.2.2

Secondary objectives of the trial

to assess NK cell frequency, NK cell cytotoxicity and the cytokine production, percentage immature NK cells/total NK cells at all time points, NK cell activation, NK cell maturation and activation in relation to clinically detectable therapeutic effect

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Definite diagnosis of RRMS according to the 2010 revised McDonald criteria (Polman et al., 2011)
• 18 to 65 years old
• Indication for on-label treatment with fingolimod (Gilenya®) ac-cording to the current approval
• EDSS score ≤ 6,0
• Neurological stable with no evidence of relapse or corticosteroid treatment within 30 days prior to screening
• Ability to provide written informed consent
• Highly effective contraception (Pearl Index < 1), reliable absti-nence from any heterosexual relationships, or sterilization of the only partner in women of childbearing potential
• Negative pregnancy test (HCG rapid test in the urine) at screen-ing and baseline in women of childbearing potential

E.4

Principal exclusion criteria

• Patients with MS manifestations other than RRMS
• Patients with known contraindications to Gilenya® according to the current “Fachinformation”, in particular
• Immunodeficiency syndrome
• Increased risk of opportunistic infections
• Severe active or chronic active infections (hepatitis, tubercu-losis)
• History or presence of malignancy (other than localized basal or squamous cell carcinoma of the skin).Severe liver dysfunction (Child Pugh C)
• Hypersensitivity against active or any other compound of study medication
• 2nd degree Mobitz Type II or higher degree AV block, Sick-sinus syndrome, or Sinu-atrial heart block, Significant QT pro-longation (QTc>470 msec (female) or >450 msec (males))
• History of symptomatic bradycardia or recurrent syncope, known ischaemic heart disease, cerebrovascular disease, history of my-ocardial infarction, hypokalaemia, congestive heart failure, history of cardiac arrest, uncontrolled hypertension, or severe sleep ap-neaPatients with clinically significant liver, kidney or bone marrow dysfunction, defined by the following laboratory values at the time of screening:
• HB <8.5 g / dl
• WBC <2.5 / nl
• platelets <100/nl
• creatinine clearance by Cockroft-Gault formula: Cl <110ml/min (men) and Cl <95ml/min (women), from age of 30 limit drops 10ml/min per decade
• AST / ALT> 3.5 times higher than the upper reference value
• bilirubine> 2.0 mg / dl
• Patients without a history of varicella or without vaccination against varicella zoster virus (VZV) and VZV negative antibody serology
• Pregnancy or lactation

E.5 End points

E.5.1

Primary end point(s)

Status of NK cell maturation, defined as the ratio immature NK cells /total NK cells (percentage), before fingolimod treatment vs. after 12 months of treatment (V4). The maturation status is determined by the expression of certain cell surface markers which can be evaluated by flow cytometry.

E.5.1.1

Timepoint(s) of evaluation of this end point

after 12 months treatment (pre-post)

E.5.2

Secondary end point(s)

NK cell frequency at all time points (determined by flow cytometry), percentage immature NK cells/total NK cells at all time points, NK cell activation (expression of certain cell surface markers determined by flow cytometry) at all time points, NK cell maturation and activation in relation to clinically detectable therapeutic effect (determined a) by annual relapse rate over study period vs. annualized relapse rate in the preceding two years; and b) by the development of disability (determined by Expanded Disability StatusScale (EDSS) during treatment with fingolimod), NK cell cytotoxicity and the cytokine production (IL-15, IL-13, IL-5, GM-CSF, IFN-gamma). These will be determined by intracellular flow cytometry or ELISA, respectively.

E.5.2.1

Timepoint(s) of evaluation of this end point

at all time points and after 12 months treatment (pre-post)

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

longitudinal, pre-post design

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

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

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

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

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.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, routine

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

2012-12-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-02-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-08-03

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