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Clinical Trial Results:
A 32-week, monocentric, exploratory, single arm study to assess immune function and MRI disease activity in patients with relapsing remitting multiple sclerosis (RRMS) transferred from previous treatment with Natalizumab to Gilenya® (Fingolimod)

Summary
EudraCT number	2013-004616-21
Trial protocol	DE
Global end of trial date	12 Feb 2016

Results information
Results version number	v1(current)
This version publication date	10 Mar 2017
First version publication date	10 Mar 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CFTY720D2415T | V1.00 | 04-Dec-2013

ISRCTN number

US NCT number

NCT02325440

WHO universal trial number (UTN)

Other trial identifiers

Sponsor code: UKM12_0037

Sponsor organisation name

Universitätsklinikum Münster

Sponsor organisation address

Albert-Schweitzer-Campus 1, Münster, Germany, 48149

Public contact

Head of Administrative Department, Universitätsklinikum Münster, 0049 251 835 5967, dorothee.kreuznacht@ukmuenster.de

Scientific contact

Coordinating Investigator, Universitätsklinikum Münster, 0049 25183444-52, LuisaHildegard.Klotz@ukmuenster.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

03 Feb 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Feb 2016

Global end of trial reached?

Yes

Global end of trial date

12 Feb 2016

Was the trial ended prematurely?

Main objective of the trial

Evaluation of changes in the reconstitution of immune surveillance over time upon switching from natalizumab to fingolimod assessed by a change in the expression of CD49d. Evaluation of changes in the migratory capacity of immune cells/PBMCs upon switching from natalizumab to fingolimod in an in-vitro model of the blood-brain-barrier (BBB). Evaluation of changes in paraclinical disease activity over time upon switching from natalizumab to fingolimod assessed by MRI

Protection of trial subjects

Safety monitoring (adverse Events, serious adverse Events, adverse drug reactions) Continous assessment of laboratory values (blood/urine)

Background therapy

N/A

Evidence for comparator

N/A

Actual start date of recruitment

03 Mar 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 15

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

15 patients were enrolled. The duration of the recruitment phase was one year. First patient was enrolled on 22-Apr-2014 (FPFV) and last patient was enrolled on 15-Apr-2015 (LPFV).

Screening details

Suitable patients were selected by the investigator. 15 patients were screened. One of the patients was initially deemed screening failure, but re-screened at a later point of time and subsequently enrolled.

Period 1 title

Natalizumab - Washout

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Treatment arm

Arm description

One final dose of natalizumab 300mg followed by an 8-week washout phase

Arm type

Experimental

Investigational medicinal product name

Natalizumab

Investigational medicinal product code

EU/1/06/346/001

Other name

Tysabri

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

300 mg i.v. (once at baseline);

Number of subjects in period 1	Treatment arm
Started	15
Completed	15

Period 2 title

Fingolimod Treatment

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Treatment arm

Arm description

24-week treatment phase with fingolimod 0.5mg o.i.d.

Arm type

Experimental

Investigational medicinal product name

Fingolimod

Investigational medicinal product code

EU/1/11/677/001-005

Other name

Gilenya

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

0.5 mg p.o. (o.i.d)

Number of subjects in period 2	Treatment arm
Started	15
Completed	14
Not completed	1
Serious adverse event	1

Period 3 title

Follow-up

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Treatment arm

Arm description

Optional 8-week follow-up phase

Arm type

Optional follow-up

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3	Treatment arm
Started	14
Completed	13
Not completed	1
Rejection of optional follow-up phase	1

Baseline characteristics

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Reporting group title

Natalizumab - Washout

Reporting group description

Reporting group values	Natalizumab - Washout	Total
Number of subjects	15	15
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	15	15
From 65-84 years	0	0
85 years and over	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	38.9 ± 9.2	-
Gender categorical
Units: Subjects
Female	11	11
Male	4	4
Ethnicity
Units: Subjects
Caucasian	15	15
Weight
Weight
Units: kg
arithmetic mean (standard deviation)	82.5 ± 22.5	-
Body-Mass-Index (BMI)
Body-Mass-Index (BMI)
Units: kg/m2
arithmetic mean (standard deviation)	27.6 ± 7.5	-
Height
Height
Units: cm
arithmetic mean (standard deviation)	172.9 ± 7.3	-

End points

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Reporting group title

Treatment arm

Reporting group description

One final dose of natalizumab 300mg followed by an 8-week washout phase

Reporting group title

Treatment arm

Reporting group description

24-week treatment phase with fingolimod 0.5mg o.i.d.

Reporting group title

Treatment arm

Reporting group description

Optional 8-week follow-up phase

Subject analysis set title

FAS (Baseline)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Set - Population (Baseline)

Subject analysis set title

FAS - (EOS; Immunology)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Set - Population (EOS | Immunology)

Subject analysis set title

FAS - (EOS | DTI)

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Set - Population (EOS | DTI)

Primary: Changes in expression of marker CD49d/CD4+ on peripheral blood mononuclear cells (PBMC) from week 0 to week 32

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End point title

Changes in expression of marker CD49d/CD4+ on peripheral blood mononuclear cells (PBMC) from week 0 to week 32

End point description

First co-primary endpoint: Difference in the expression of marker CD49d (mean fluorescence intensity [MFI]) between the measurement at EOS (week 32) and the baseline value (week 0)

End point type

Primary

End point timeframe

32 weeks

End point values	FAS (Baseline)	FAS - (EOS; Immunology)
Number of subjects analysed	14	14 ^[1]
Units: Mean Fluorescence Intensity (MFI)
arithmetic mean (standard deviation)	6.03 ± 1.05	10.11 ± 3.71

Notes
[1] - Data for one patient in the FAS was missing at week 32 (EOS)

Paired t-test

Statistical analysis description

Paired t-test with a significance level of 0.05%

Comparison groups

FAS (Baseline) v FAS - (EOS; Immunology)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

t-test, 2-sided

Confidence interval

Primary: Changes in migratory capacity of immune cells/peripheral blood mononuclear cells (PBMCs) in an in-vitro model of the blood-brain-barrier (BBB) from week 0 to week 32

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End point title

Changes in migratory capacity of immune cells/peripheral blood mononuclear cells (PBMCs) in an in-vitro model of the blood-brain-barrier (BBB) from week 0 to week 32

End point description

Second co-primary endpoint: Difference between migratory capacities of unstimulated CD4+ cells at EOS (week 32) compared to baseline (week 0)

End point type

Primary

End point timeframe

32 weeks

End point values	FAS (Baseline)	FAS - (EOS; Immunology)
Number of subjects analysed	14	14 ^[2]
Units: Fluorescence intensity
arithmetic mean (standard deviation)	1.44 ± 0.54	3.33 ± 2.71

Notes
[2] - Data for one patient in the FAS was missing at week 32 (EOS)

Paired t-test

Statistical analysis description

Paired t-test with a significance level of 0.05%

Comparison groups

FAS (Baseline) v FAS - (EOS; Immunology)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.028

Method

t-test, 2-sided

Confidence interval

Secondary: MRI Disease activity - Number of new Gd+ lesions from week 0 to week 32

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End point title

MRI Disease activity - Number of new Gd+ lesions from week 0 to week 32

End point description

Number of new Gd+ lesions counted from baseline until EOS

End point type

Secondary

End point timeframe

32 weeks

End point values	FAS - (EOS; Immunology)
Number of subjects analysed	15 ^[3]
Units: Number of new Gd+ lesions
median (inter-quartile range (Q1-Q3))	3 (0 to 6)

Notes
[3] - Data for one patient at one visit missing | Reason: Study discontinuation

No statistical analyses for this end point

Secondary: MRI disease activity - Number of new T2w lesions from week 0 to week 32

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End point title

MRI disease activity - Number of new T2w lesions from week 0 to week 32

End point description

Number of new T2w lesions counted from baseline until EOS.

End point type

Secondary

End point timeframe

32 weeks

End point values	FAS - (EOS; Immunology)
Number of subjects analysed	15 ^[4]
Units: Number of new T2w lesions
median (inter-quartile range (Q1-Q3))	1 (0 to 5)

Notes
[4] - Data for one patient at one visit missing | Reason: Study discontinuation

No statistical analyses for this end point

Secondary: MRI disease activity - Change in DTI fractional anisotropy from week 0 to week 32

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End point title

MRI disease activity - Change in DTI fractional anisotropy from week 0 to week 32

End point description

Change in DTI fractional anisotropy from baseline to EOS

End point type

Secondary

End point timeframe

32 weeks

End point values	FAS (Baseline)	FAS - (EOS \| DTI)
Number of subjects analysed	10	10 ^[5]
Units: DTI fractional anisotropy
median (inter-quartile range (Q1-Q3))	0.29 (0.28 to 0.3)	0.29 (0.29 to 0.3)

Notes
[5] - Data for five patients in the FAS were missing at week 32 (EOS)

Paired t-test

Statistical analysis description

Paired t-test with a significance level of 0.05%

Comparison groups

FAS (Baseline) v FAS - (EOS | DTI)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.975

Method

t-test, 2-sided

Confidence interval

Adverse events

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Timeframe for reporting adverse events

Adverse Events were recorded from baseline (week 0) until end of follow-up phase (week 40)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Safety Set

Reporting group description

Full-Analysis-Set = Safety Set

Serious adverse events	Safety Set
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 15 (20.00%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Investigations
Nuclear magnetic resonance imaging brain abnormal
subjects affected / exposed	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Nervous system disorders
Multiple sclerosis relapse
subjects affected / exposed	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Safety Set
Total subjects affected by non serious adverse events
subjects affected / exposed	15 / 15 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Vascular disorders
Thrombophlebitis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	3 / 15 (20.00%)
occurrences all number	4
Pyrexia
subjects affected / exposed	3 / 15 (20.00%)
occurrences all number	3
Reproductive system and breast disorders
Menorrhagia
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	3 / 15 (20.00%)
occurrences all number	4
Psychiatric disorders
Depressed mood
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Depression
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Aspartate aminotransferase increased
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Blood triglycerides increased
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Hepatic enzyme increased
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Lymphocyte count decreased
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Nuclear magnetic resonance imaging brain abnormal
subjects affected / exposed	7 / 15 (46.67%)
occurrences all number	15
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Concussion
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Peroneal nerve injury
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Post lumbar puncture syndrome
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Nervous system disorders
Cervicobrachial syndrome
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Headache
subjects affected / exposed	6 / 15 (40.00%)
occurrences all number	13
Multiple sclerosis relapse
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Muscle spasticity
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Eye disorders
Vision blurred
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 15 (20.00%)
occurrences all number	3
Enteritis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Nausea
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Stomatitis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	2
Toothache
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Skin and subcutaneous tissue disorders
Skin fissures
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Micturition urgency
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	3
Pain in extremity
subjects affected / exposed	3 / 15 (20.00%)
occurrences all number	3
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Dental fistula
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Conjunctivitis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Gastroenteritis
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	2
Herpes simplex
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	4
Nasopharyngitis
subjects affected / exposed	13 / 15 (86.67%)
occurrences all number	24
Oral herpes
subjects affected / exposed	2 / 15 (13.33%)
occurrences all number	4
Periodontitis
subjects affected / exposed	1 / 15 (6.67%)
occurrences all number	1
Urinary tract infection
subjects affected / exposed	4 / 15 (26.67%)
occurrences all number	6

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/26099927

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Clinical trials

Clinical Trial Results:
A 32-week, monocentric, exploratory, single arm study to assess immune function and MRI disease activity in patients with relapsing remitting multiple sclerosis (RRMS) transferred from previous treatment with Natalizumab to Gilenya® (Fingolimod)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Changes in expression of marker CD49d/CD4+ on peripheral blood mononuclear cells (PBMC) from week 0 to week 32

Primary: Changes in expression of marker CD49d/CD4+ on peripheral blood mononuclear cells (PBMC) from week 0 to week 32

Primary: Changes in migratory capacity of immune cells/peripheral blood mononuclear cells (PBMCs) in an in-vitro model of the blood-brain-barrier (BBB) from week 0 to week 32

Primary: Changes in migratory capacity of immune cells/peripheral blood mononuclear cells (PBMCs) in an in-vitro model of the blood-brain-barrier (BBB) from week 0 to week 32

Secondary: MRI Disease activity - Number of new Gd+ lesions from week 0 to week 32

Secondary: MRI Disease activity - Number of new Gd+ lesions from week 0 to week 32

Secondary: MRI disease activity - Number of new T2w lesions from week 0 to week 32

Secondary: MRI disease activity - Number of new T2w lesions from week 0 to week 32

Secondary: MRI disease activity - Change in DTI fractional anisotropy from week 0 to week 32

Secondary: MRI disease activity - Change in DTI fractional anisotropy from week 0 to week 32

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Finland
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Germany
Greece
Hungary
Iceland
Ireland
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Luxembourg
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Netherlands
Norway
Poland
Portugal
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Slovenia
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Outside EU/EEA

Clinical trials

Clinical Trial Results: A 32-week, monocentric, exploratory, single arm study to assess immune function and MRI disease activity in patients with relapsing remitting multiple sclerosis (RRMS) transferred from previous treatment with Natalizumab to Gilenya® (Fingolimod)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Changes in expression of marker CD49d/CD4+ on peripheral blood mononuclear cells (PBMC) from week 0 to week 32

Primary: Changes in expression of marker CD49d/CD4+ on peripheral blood mononuclear cells (PBMC) from week 0 to week 32

Primary: Changes in migratory capacity of immune cells/peripheral blood mononuclear cells (PBMCs) in an in-vitro model of the blood-brain-barrier (BBB) from week 0 to week 32

Primary: Changes in migratory capacity of immune cells/peripheral blood mononuclear cells (PBMCs) in an in-vitro model of the blood-brain-barrier (BBB) from week 0 to week 32

Secondary: MRI Disease activity - Number of new Gd+ lesions from week 0 to week 32

Secondary: MRI Disease activity - Number of new Gd+ lesions from week 0 to week 32

Secondary: MRI disease activity - Number of new T2w lesions from week 0 to week 32

Secondary: MRI disease activity - Number of new T2w lesions from week 0 to week 32

Secondary: MRI disease activity - Change in DTI fractional anisotropy from week 0 to week 32

Secondary: MRI disease activity - Change in DTI fractional anisotropy from week 0 to week 32

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A 32-week, monocentric, exploratory, single arm study to assess immune function and MRI disease activity in patients with relapsing remitting multiple sclerosis (RRMS) transferred from previous treatment with Natalizumab to Gilenya® (Fingolimod)