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Clinical Trial Results:
A 24-week, multicenter, exploratory, two arm study to assess the effect of Dimethyl fumarate on Immune-Modulatory Action on T cells in patients with relapsing remitting Multiple Sclerosis

Summary
EudraCT number	2014-003481-25
Trial protocol	DE
Global end of trial date	07 May 2018

Results information
Results version number	v1(current)
This version publication date	04 Jan 2020
First version publication date	04 Jan 2020
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

DIMAT-MS

ISRCTN number

US NCT number

WHO universal trial number (UTN)

U1111-1164-2476

Sponsor organisation name

Universitätsklinikum Münster

Sponsor organisation address

Albert-Schweitzer-Campus 1, Gebäude D5, Münster, Germany, 48149

Public contact

Klinik für Allgemeine Neurologie, Universitätsklinikum Münster, Luisa.Klotz@ukmuenster.de

Scientific contact

Klinik für Allgemeine Neurologie, Universitätsklinikum Münster, Luisa.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

07 May 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

07 May 2018

Global end of trial reached?

Yes

Global end of trial date

07 May 2018

Was the trial ended prematurely?

Main objective of the trial

This is an exploratory study design, which allows analysis of multiple immune parameters derived from peripheral blood mononuclear cells (PBMCs) from patients with relapsing remitting multiple sclerosis before and during immune-modulatory treatment with dimethyl fumarate (Tecfidera) in comparison to PBMCs from healthy subjects.

Protection of trial subjects

The study was conducted in accordance with the Declaration of Helsinki and the ICH Guidelines in Good Clinical Practice. The study was not started before the competent ethics committee had given a favorable opinion. Written informed consent was obtained from all patients and the study was only conducted as approved by the Ethics committee and the competent authority. Amendments were only implemented after approval.

Background therapy

A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses at any time during the study as clinically warranted. Steroid treatment should consist of 3-5 days and up to 1,000 mg methylprednisolone/day intravenously.

Evidence for comparator

Healthy subjects were used as a reference group and were not treated.

Actual start date of recruitment

05 Jun 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 67

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

The RRMS (relapsing remitting multiple sclerosis) patients were recruited from three university hospitals and one neurological specialist practice throughout Germany. Healthy subjects were only recruited at the Universitätsklinikum Münster. The recruitment period was from June 2015 to January 2018.

Screening details

The study included untreated healthy subjects and patients with RRMS according to the 2010 revised McDonald`s criteria who were either treatment-naïve (i.e. no dimethyl fumarate treatment for at least 1 month) or willing to switch from conventional first-line immunomodulatory therapy (beta-interferons, glatiramer acetate) to dimethyl fumarate.

Number of subjects started

Number of subjects completed

Reason: Number of subjects

Consent withdrawn by subject: 1

Reason: Number of subjects

Not meeting inclusion criteria: 8

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Dimethyl fumarate (DMF) (RRMS patients)

Arm description

RRMS patients treated with dimethyl fumarate.

Arm type

Experimental

Investigational medicinal product name

Tecfidera

Investigational medicinal product code

Other name

Dimethyl fumarate

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

RRMS patients received dimethyl fumarate (Tecfidera) from week 0 to week 24. Dimethyl fumarate (Tecfidera®) treatment was initiated by daily administration of 120 mg Tecfidera® p.o. in the morning in week 0. At week 1, the dose was increased to 120 mg Tecfidera® p.o. twice daily, split into a morning and an evening dose. At week 2, the daily dose was further increased to 240 mg Tecfidera® p.o. in the morning and 120 mg Tecfidera® p.o. in the evening. Finally at week 3, the dose was increased to the final daily dose of 240 mg Tecfidera® p.o. in the morning and 240 mg Tecfidera® p.o. in the evening and maintained throughout the study. Study participants were able to perform an optional 24-week follow-up Phase. No study treatment was performed in the follow-up phase. However, RRMS patients were able to continue treatment with dimethyl fumarate (Tecfidera).

No treatment (Healthy subjects)

Arm description

Healthy subjects who have not been treated.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1 ^[1]	Dimethyl fumarate (DMF) (RRMS patients)	No treatment (Healthy subjects)
Started	42	16
End of core study phase (Week 24)	37	14
Completed	33	14
Not completed	9	2
Consent withdrawn by subject	1	1
Relapse	1	-
End of study after core study phase	2	-
Adverse event, non-fatal	2	-
Pregnancy	2	1
Lost to follow-up	1	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 51 RRMS patients were enrolled in the study and assessed for eligibility. Because 8 patients did not meet the inclusion criteria and one patient withdrew consent before start of treatment, only 42 RRMS patients entered the baseline period.

Baseline characteristics

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Reporting group title

Dimethyl fumarate (DMF) (RRMS patients)

Reporting group description

RRMS patients treated with dimethyl fumarate.

Reporting group title

No treatment (Healthy subjects)

Reporting group description

Healthy subjects who have not been treated.

Reporting group values	Dimethyl fumarate (DMF) (RRMS patients)	No treatment (Healthy subjects)	Total
Number of subjects	42	16	58
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	42	16	58
From 65-84 years	0	0	0
85 years and over	0	0	0
Gender categorical
Units: Subjects
Female	28	11	39
Male	14	5	19

End points

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Reporting group title

Dimethyl fumarate (DMF) (RRMS patients)

Reporting group description

RRMS patients treated with dimethyl fumarate.

Reporting group title

No treatment (Healthy subjects)

Reporting group description

Healthy subjects who have not been treated.

Primary: Number of lymphocytes in PBMCs

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End point title

Number of lymphocytes in PBMCs ^[1] ^[2]

End point description

The number of lymphocytes in the PBMC (peripheral blood mononuclear cell) population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Lymphocytes (percent of PBMCs)
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	79.13 (74.27 to 84.97)
Month 2 (n = 19)	76.78 (73.23 to 85.05)
Month 4 (n = 19)	77.14 (72.71 to 81.83)
Month 6 (n = 34)	72.75 (68.18 to 81.91)
Month 11 (n = 19)	73.76 (68.59 to 80.86)

No statistical analyses for this end point

Primary: Absolute change of lymphocytes in PBMCs

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End point title

Absolute change of lymphocytes in PBMCs ^[3] ^[4]

End point description

Absolute change of lymphocytes from baseline (month 0) within the PBMC population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Lymphocytes (percent of PBMCs)
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-2.13 (-4.62 to 2.74)
Month 4 (n = 19)	-3.09 (-11.95 to 3.22)
Month 6 (n = 34)	-7.16 (-16.40 to 2.98)
Month 11 (n = 19)	-3.50 (-13.94 to 2.15)

No statistical analyses for this end point

Primary: Number of monocytes in PBMCs

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End point title

Number of monocytes in PBMCs ^[5] ^[6]

End point description

The number of monocytes in the PBMC population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Monocytes (percent of PBMCs)
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	20.83 (14.96 to 25.66)
Month 2 (n = 19)	23.20 (14.91 to 26.71)
Month 4 (n = 19)	22.83 (18.09 to 27.11)
Month 6 (n = 34)	27.20 (17.62 to 31.74)
Month 11 (n = 19)	26.08 (19.10 to 31.33)

No statistical analyses for this end point

Primary: Absolute change of monocytes in PBMCs

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End point title

Absolute change of monocytes in PBMCs ^[7] ^[8]

End point description

Absolute change of monocytes from baseline (month 0) within the PBMC population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Monocytes (percent of PBMCs)
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	2.15 (-2.72 to 4.54)
Month 4 (n = 19)	2.93 (-3.22 to 11.96)
Month 6 (n = 34)	7.13 (-2.98 to 16.24)
Month 11 (n = 19)	3.49 (-2.29 to 13.97)

No statistical analyses for this end point

Primary: Number of T cells in lymphocytes

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End point title

Number of T cells in lymphocytes ^[9] ^[10]

End point description

The number of T cells in the lymphocyte population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: T cells (percent of Lymphocytes)
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	69.17 (56.87 to 72.39)
Month 2 (n = 19)	66.47 (63.96 to 72.69)
Month 4 (n = 19)	69.68 (63.21 to 71.54)
Month 6 (n = 34)	64.53 (53.87 to 71.01)
Month 11 (n = 19)	65.23 (59.75 to 72.86)

No statistical analyses for this end point

Primary: Absolute change of T cells in lymphocytes

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End point title

Absolute change of T cells in lymphocytes ^[11] ^[12]

End point description

Absolute change of T cells from baseline (month 0) within the lymphocytes population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: T cells (percent of Lymphocytes)
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-0.21 (-3.65 to 3.30)
Month 4 (n = 19)	2.61 (-2.69 to 6.68)
Month 6 (n = 34)	-0.91 (-10.28 to 4.37)
Month 11 (n = 19)	0.77 (-4.19 to 7.19)

No statistical analyses for this end point

Primary: Number of CD4 T cells in T cells

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End point title

Number of CD4 T cells in T cells ^[13] ^[14]

End point description

The number of CD4 T cells in the T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: CD4 T cells (percent of T cells)
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	72.10 (67.29 to 79.42)
Month 2 (n = 19)	74.66 (66.82 to 81.78)
Month 4 (n = 19)	80.64 (69.42 to 86.15)
Month 6 (n = 34)	76.47 (72.55 to 82.83)
Month 11 (n = 19)	80.70 (69.58 to 84.73)

No statistical analyses for this end point

Primary: Absolute change of CD4 T cells in T cells

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End point title

Absolute change of CD4 T cells in T cells ^[15] ^[16]

End point description

Absolute change of CD4 T cells from baseline (month 0) within the T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: CD4 T cells (percent of T cells)
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	0.49 (-1.61 to 2.88)
Month 4 (n = 19)	2.60 (-1.75 to 5.52)
Month 6 (n = 34)	4.31 (0.37 to 6.02)
Month 11 (n = 19)	3.62 (1.65 to 9.15)

No statistical analyses for this end point

Primary: Number of CD8 T cells in T cells

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End point title

Number of CD8 T cells in T cells ^[17] ^[18]

End point description

The number of CD8 T cells in the T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: CD8 T cells (percent of T cells)
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	17.78 (13.55 to 23.34)
Month 2 (n = 19)	16.62 (11.03 to 25.79)
Month 4 (n = 19)	12.96 (7.28 to 25.02)
Month 6 (n = 34)	15.85 (9.84 to 20.16)
Month 11 (n = 19)	12.44 (8.00 to 22.06)

No statistical analyses for this end point

Primary: Absolute change of CD8 T cells in T cells

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End point title

Absolute change of CD8 T cells in T cells ^[19] ^[20]

End point description

Absolute change of CD8 T cells from baseline (month 0) within the T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: CD8 T cells (percent of T cells)
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	0.09 (-2.15 to 2.04)
Month 4 (n = 19)	-2.13 (-4.01 to 0.30)
Month 6 (n = 34)	-2.18 (-5.16 to -0.56)
Month 11 (n = 19)	-3.63 (-8.05 to -1.22)

No statistical analyses for this end point

Primary: Number of naive CD4 T cells in CD4 T cells

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End point title

Number of naive CD4 T cells in CD4 T cells ^[21] ^[22]

End point description

The number of naive CD4 T cells in the CD4 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per µL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	94.78 (81.69 to 95.99)
Month 2 (n = 19)	93.82 (91.63 to 96.14)
Month 4 (n = 19)	94.59 (91.90 to 95.73)
Month 6 (n = 34)	91.82 (81.57 to 95.73)
Month 11 (n = 19)	94.35 (91.52 to 95.72)

No statistical analyses for this end point

Primary: Absolute change of naive CD4 T cells in CD4 T cells

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End point title

Absolute change of naive CD4 T cells in CD4 T cells ^[23] ^[24]

End point description

Absolute change of naive CD4 T cells from baseline (month 0) within the CD4 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per µL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-0.93 (-2.61 to 0.91)
Month 4 (n = 19)	-0.73 (-2.68 to 1.14)
Month 6 (n = 34)	-0.16 (-5.57 to 4.72)
Month 11 (n = 19)	-0.46 (-5.63 to 6.38)

No statistical analyses for this end point

Primary: Number of central memory CD4 T cells in CD4 T cells

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End point title

Number of central memory CD4 T cells in CD4 T cells ^[25] ^[26]

End point description

The number of central memory CD4 T cells in the CD4 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per µL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	137.04 (67.28 to 262.87)
Month 2 (n = 19)	145.88 (77.15 to 204.24)
Month 4 (n = 19)	88.42 (46.43 to 232.67)
Month 6 (n = 34)	71.08 (44.93 to 168.54)
Month 11 (n = 17)	62.28 (41.54 to 95.99)

No statistical analyses for this end point

Primary: Absolute change of central memory CD4 T cells in CD4 T cells

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End point title

Absolute change of central memory CD4 T cells in CD4 T cells ^[27] ^[28]

End point description

Absolute change of central memory CD4 T cells from baseline (month 0) within the CD4 T cell population during DMF Treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-28.74 (-57.11 to 8.29)
Month 4 (n = 19)	-44.34 (-97.71 to 17.85)
Month 6 (n = 34)	-69.46 (-120.78 to 9.88)
Month 11 (n = 17)	-83.50 (-167.00 to -56.30)

No statistical analyses for this end point

Primary: Number of effector memory CD4 T cells in CD4 T cells

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End point title

Number of effector memory CD4 T cells in CD4 T cells ^[29] ^[30]

End point description

The number of effector memory CD4 T cells in the CD4 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	113.40 (53.26 to 155.11)
Month 2 (n = 19)	126.91 (57.30 to 162.66)
Month 4 (n = 19)	67.56 (43.60 to 128.14)
Month 6 (n = 34)	59.14 (18.41 to 123.99)
Month 11 (n = 17)	34.47 (17.07 to 53.70)

No statistical analyses for this end point

Primary: Absolute change of effector memory CD4 T cells in CD4 T cells

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End point title

Absolute change of effector memory CD4 T cells in CD4 T cells ^[31] ^[32]

End point description

Absolute change of memory CD4 T cells from baseline (month 0) within the CD4 T cell population during DMF Treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	12.96 (-59.83 to 32.89)
Month 4 (n = 19)	-46.18 (-77.48 to 10.63)
Month 6 (n = 34)	-64.68 (-94.91 to -4.67)
Month 11 (n = 17)	-86.80 (-115.07 to -49.35)

No statistical analyses for this end point

Primary: Number of CD4 RTEs in CD4 T cells

Top of page

End point title

Number of CD4 RTEs in CD4 T cells ^[33] ^[34]

End point description

The number of CD4 RTEs (Recent Thymic Emigrants) in the CD4 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	248.37 (177.33 to 395.43)
Month 2 (n = 19)	241.99 (186.56 to 323.91)
Month 4 (n = 19)	245.58 (152.32 to 307.67)
Month 6 (n = 34)	200.22 (126.39 to 332.06)
Month 11 (n = 17)	225.50 (139.55 to 316.22)

No statistical analyses for this end point

Primary: Absolute change of CD4 RTEs in CD4 T cells

Top of page

End point title

Absolute change of CD4 RTEs in CD4 T cells ^[35] ^[36]

End point description

Absolute change of CD4 RTEs from baseline (month 0) within the CD4 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[35] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-33.79 (-79.50 to 31.02)
Month 4 (n = 19)	-5.73 (-110.75 to 19.93)
Month 6 (n = 34)	-47.01 (-130.13 to 18.15)
Month 11 (n = 17)	-39.23 (-69.11 to 10.93)

No statistical analyses for this end point

Primary: Number of naive CD8 T cells in CD8 T cells

Top of page

End point title

Number of naive CD8 T cells in CD8 T cells ^[37] ^[38]

End point description

The number of naive CD8 T cells in the CD8 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	60.85 (37.58 to 138.80)
Month 2 (n = 19)	65.60 (22.20 to 126.16)
Month 4 (n = 19)	40.48 (22.08 to 97.46)
Month 6 (n = 34)	37.74 (22.53 to 77.30)
Month 11 (n = 17)	37.70 (21.14 to 81.52)

No statistical analyses for this end point

Primary: Absolute change of naive CD8 T cells in CD8 T cells

Top of page

End point title

Absolute change of naive CD8 T cells in CD8 T cells ^[39] ^[40]

End point description

Absolute change of naive CD8 T cells from baseline (month 0) within the CD8 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[39] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-9.70 (-31.05 to 7.18)
Month 4 (n = 19)	-15.71 (-67.91 to 2.29)
Month 6 (n = 34)	-18.93 (-49.83 to 0.89)
Month 11 (n = 17)	-25.49 (-55.25 to -4.10)

No statistical analyses for this end point

Primary: Number of central memory CD8 T cells in CD8 T cells

Top of page

End point title

Number of central memory CD8 T cells in CD8 T cells ^[41] ^[42]

End point description

The number of central memory CD8 T cells in the CD8 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[41] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	1.97 (0.75 to 4.72)
Month 2 (n = 19)	1.73 (0.67 to 2.80)
Month 4 (n = 19)	0.89 (0.63 to 2.31)
Month 6 (n = 34)	0.64 (0.36 to 2.25)
Month 11 (n = 17)	0.35 (0.25 to 0.69)

No statistical analyses for this end point

Primary: Absolute change of central memory CD8 T cells in CD8 T cells

Top of page

End point title

Absolute change of central memory CD8 T cells in CD8 T cells ^[43] ^[44]

End point description

Absolute change of central memory CD8 T cells from baseline (month 0) within the CD8 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[43] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-0.81 (-1.37 to 0.02)
Month 4 (n = 19)	-0.86 (-1.91 to 0.15)
Month 6 (n = 34)	-1.16 (-1.96 to 0.16)
Month 11 (n = 17)	-1.22 (-2.29 to -0.52)

No statistical analyses for this end point

Primary: Number of effector memory CD8 T cells in CD8 T cells

Top of page

End point title

Number of effector memory CD8 T cells in CD8 T cells ^[45] ^[46]

End point description

The number of effector memory CD8 T cells in the CD8 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[45] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	14.19 (7.65 to 27.84)
Month 2 (n = 19)	11.65 (6.62 to 22.08)
Month 4 (n = 19)	6.97 (3.53 to 21.58)
Month 6 (n = 34)	5.95 (2.60 to 14.22)
Month 11 (n = 17)	2.30 (1.63 to 5.61)

No statistical analyses for this end point

Primary: Absolute change of effector memory CD8 T cells in CD8 T cells

Top of page

End point title

Absolute change of effector memory CD8 T cells in CD8 T cells ^[47] ^[48]

End point description

Absolute change of effector memory CD8 T cells from baseline (month 0) within the CD8 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[47] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-1.05 (-10.45 to 2.85)
Month 4 (n = 19)	-4.77 (-11.87 to -1.17)
Month 6 (n = 34)	-8.58 (-16.34 to -0.57)
Month 11 (n = 17)	-12.49 (-24.05 to -4.54)

No statistical analyses for this end point

Primary: Number of TEMRA in CD8 T cells

Top of page

End point title

Number of TEMRA in CD8 T cells ^[49] ^[50]

End point description

The number of TEMRAs (Effector Memory RA T cells) in the CD8 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[49] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	14.01 (6.36 to 26.86)
Month 2 (n = 19)	5.40 (4.34 to 16.98)
Month 4 (n = 19)	5.96 (3.55 to 23.16)
Month 6 (n = 34)	7.27 (3.55 to 11.26)
Month 11 (n = 17)	3.14 (1.75 to 4.86)

No statistical analyses for this end point

Primary: Absolute change of TEMRA in CD8 T cells

Top of page

End point title

Absolute change of TEMRA in CD8 T cells ^[51] ^[52]

End point description

Absolute change of TEMRAs from baseline (month 0) within the CD8 T cell population during DMF treatment.

End point type

Primary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[51] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since this is an explorative study, the endpoints were only evaluated descriptively.
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-1.00 (-6.16 to 0.39)
Month 4 (n = 19)	-2.30 (-8.56 to -0.41)
Month 6 (n = 34)	-4.79 (-15.47 to 1.82)
Month 11 (n = 17)	-6.02 (-14.17 to -2.77)

No statistical analyses for this end point

Secondary: Number of GM-CSF-producing CD4 T cells

Top of page

End point title

Number of GM-CSF-producing CD4 T cells ^[53]

End point description

CD4 T cells were stimulated with leukocyte activation Cocktail for 6 hours and analyzed by flow cytometry for the intracellular amount of granulocyte-macrophage colony-stimulating factor (GM-CSF).

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	1.43 (0.94 to 1.76)
Month 2 (n = 19)	1.13 (0.89 to 1.65)
Month 4 (n = 19)	0.97 (0.71 to 1.36)
Month 6 (n = 34)	1.02 (0.68 to 1.56)
Month 11 (n = 19)	0.98 (0.75 to 1.25)

No statistical analyses for this end point

Secondary: Absolute change of GM-CSF-producing CD4 T cells

Top of page

End point title

Absolute change of GM-CSF-producing CD4 T cells ^[54]

End point description

CD4 T cells were stimulated with leukocyte activation Cocktail for 6 hours and analyzed by flow cytometry for the intracellular amount of granulocyte-macrophage colony-stimulating factor (GM-CSF).

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-0.24 (-0.63 to 0.18)
Month 4 (n = 19)	-0.44 (-0.87 to -0.15)
Month 6 (n = 34)	-0.16 (-0.81 to 0.37)
Month 11 (n = 19)	-0.47 (-0.65 to -0.11)

No statistical analyses for this end point

Secondary: Number of IFN-gamma-producing CD4 T cells

Top of page

End point title

Number of IFN-gamma-producing CD4 T cells ^[55]

End point description

CD4 T cells were stimulated with leukocyte activation Cocktail for 6 hours and analyzed by flow cytometry for the intracellular amount of interferon (IFN)-gamma.

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	10.15 (7.02 to 13.78)
Month 2 (n = 19)	11.25 (4.20 to 15.58)
Month 4 (n = 19)	7.94 (2.13 to 12.24)
Month 6 (n = 34)	6.97 (2.27 to 10.06)
Month 11 (n = 19)	3.15 (2.04 to 8.85)

No statistical analyses for this end point

Secondary: Absolute change of IFN-gamma-producing CD4 T cells

Top of page

End point title

Absolute change of IFN-gamma-producing CD4 T cells ^[56]

End point description

CD4 T cells were stimulated with leukocyte activation Cocktail for 6 hours and analyzed by flow cytometry for the intracellular amount of interferon (IFN)-gamma.

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-0.12 (-3.02 to 2.29)
Month 4 (n = 19)	-2.34 (-5.84 to 1.50)
Month 6 (n = 34)	-3.73 (-6.81 to -0.04)
Month 11 (n = 19)	-4.85 (-8.34 to -1.24)

No statistical analyses for this end point

Secondary: Number of IL-17A-producing CD4 T cells

Top of page

End point title

Number of IL-17A-producing CD4 T cells ^[57]

End point description

CD4 T cells were stimulated with leukocyte activation Cocktail for 6 hours and analyzed by flow cytometry for the intracellular amount of IL-17A.

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	0.84 (0.51 to 1.27)
Month 2 (n = 19)	0.81 (0.49 to 1.10)
Month 4 (n = 19)	0.75 (0.41 to 0.88)
Month 6 (n = 34)	0.65 (0.40 to 0.96)
Month 11 (n = 19)	0.51 (0.26 to 0.90)

No statistical analyses for this end point

Secondary: Absolute change of IL17A-producing CD4 T cells

Top of page

End point title

Absolute change of IL17A-producing CD4 T cells ^[58]

End point description

CD4 T cells were stimulated with leukocyte activation Cocktail for 6 hours and analyzed by flow cytometry for the intracellular amount of IL17A.

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-0.07 (-0.25 to 0.13)
Month 4 (n = 19)	-0.06 (-0.36 to 0.01)
Month 6 (n = 34)	-0.24 (-0.39 to 0.01)
Month 11 (n = 19)	-0.31 (-0.52 to -0.04)

No statistical analyses for this end point

Secondary: Number of IL-4-producing CD4 T cells

Top of page

End point title

Number of IL-4-producing CD4 T cells ^[59]

End point description

CD4 T cells were stimulated with leukocyte activation Cocktail for 6 hours and analyzed by flow cytometry for the intracellular amount of IL-4.

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 0 (n = 34)	1.73 (1.28 to 2.17)
Month 2 (n = 19)	1.50 (1.27 to 2.29)
Month 4 (n = 19)	1.48 (1.16 to 1.94)
Month 6 (n = 34)	1.56 (1.18 to 2.35)
Month 11 (n = 19)	1.35 (1.10 to 1.97)

No statistical analyses for this end point

Secondary: Absolute change of IL-4-producing CD4 T cells

Top of page

End point title

Absolute change of IL-4-producing CD4 T cells ^[60]

End point description

CD4 T cells were stimulated with leukocyte activation Cocktail for 6 hours and analyzed by flow cytometry for the intracellular amount of IL-4.

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Cell count per μL
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-0.05 (-0.36 to 0.17)
Month 4 (n = 19)	-0.10 (-0.53 to 0.18)
Month 6 (n = 34)	-0.05 (-0.26 to 0.17)
Month 11 (n = 19)	-0.32 (-0.56 to 0.08)

No statistical analyses for this end point

Secondary: Absolute change of thymus derived regulatory T cells in memory CD4 T cells

Top of page

End point title

Absolute change of thymus derived regulatory T cells in memory CD4 T cells ^[61]

End point description

Absolute change of thymus derived regulatory T cells (tTreg) from baseline (month 0) within the memory CD4 T cell (CD4 Mem) population during DMF treatment.

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: tTreg (percent of CD4 Mem)
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-0.12 (-0.64 to 1.49)
Month 4 (n = 19)	0.39 (-0.48 to 1.66)
Month 6 (n = 34)	0.59 (-0.23 to 2.27)
Month 11 (n = 19)	1.78 (-0.19 to 3.32)

No statistical analyses for this end point

Secondary: Absolute change of regulatory T cells in CD4 T cells

Top of page

End point title

Absolute change of regulatory T cells in CD4 T cells ^[62]

End point description

Absolute change of regulatory T cells (Treg) from baseline (month 0) within the CD4 T cell population during DMF treatment.

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: Treg (percent of CD4 T cells)
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-2.00 (-6.97 to 2.49)
Month 4 (n = 19)	-3.96 (-9.89 to 1.32)
Month 6 (n = 34)	-7.20 (-10.68 to 0.61)
Month 11 (n = 19)	-8.49 (-13.64 to -6.67)

No statistical analyses for this end point

Secondary: Absolute change of thymus derived regulatory T cells in CD4 T cells

Top of page

End point title

Absolute change of thymus derived regulatory T cells in CD4 T cells ^[63]

End point description

Absolute change of thymus derived regulatory T cells (tTreg) from baseline (month 0) within the CD4 T cell population during DMF Treatment.

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: tTreg (percent of CD4 T cells)
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-0.15 (-0.39 to 0.42)
Month 4 (n = 19)	-0.17 (-0.57 to 0.34)
Month 6 (n = 34)	0.04 (-0.51 to 0.31)
Month 11 (n = 19)	-0.26 (-0.88 to 0.15)

No statistical analyses for this end point

Secondary: Absolute change of peripheral derived regulatory T cells in CD4 T cells

Top of page

End point title

Absolute change of peripheral derived regulatory T cells in CD4 T cells ^[64]

End point description

Absolute change of peripheral derived regulatory T cells (pTreg) from baseline (month 0) within the CD4 T cell population during DMF treatment.

End point type

Secondary

End point timeframe

Months 0, 2, 4, 6 and 11.

Notes
[64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	34
Units: pTreg (percent of CD4 T cells)
median (inter-quartile range (Q1-Q3))
Month 2 (n = 19)	-0.02 (-0.09 to 0.05)
Month 4 (n = 19)	-0.03 (-0.15 to 0.05)
Month 6 (n = 34)	-0.03 (-0.10 to 0.03)
Month 11 (n = 19)	-0.06 (-0.14 to -0.02)

No statistical analyses for this end point

Secondary: Mitochondrial energy metabolism of unstimulated (ex vivo) CD4 T cells

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End point title

Mitochondrial energy metabolism of unstimulated (ex vivo) CD4 T cells ^[65]

End point description

Measurement of mitochondrial energy metabolism (i.e. oxidative phosphorylation) of unstimulated (ex vivo) CD4 T cells using seahorse agilent technology during DMF treatment.

End point type

Secondary

End point timeframe

Months 0, 6 and 11.

Notes
[65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	14
Units: oxygen consumption rate in pmol/min
median (inter-quartile range (Q1-Q3))
Month 0 (n = 14)	60.14 (41.57 to 101.45)
Month 6 (n = 14)	62.20 (51.39 to 92.01)
Month 11 (n = 14)	65.18 (28.63 to 75.57)

No statistical analyses for this end point

Secondary: Mitochondrial energy metabolism of short-term stimulated CD4 T cells

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End point title

Mitochondrial energy metabolism of short-term stimulated CD4 T cells ^[66]

End point description

Measurement of mitochondrial energy metabolism (i.e. oxidative phosphorylation) of short-term stimulated CD4 T cells using seahorse agilent technology during DMF treatment.

End point type

Secondary

End point timeframe

Months 0, 6 and 11.

Notes
[66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	14
Units: oxygen consumption rate in pmol/min
median (inter-quartile range (Q1-Q3))
Month 0 (n = 14)	49.26 (38.33 to 69.60)
Month 6 (n = 14)	34.79 (16.78 to 57.62)
Month 11 (n = 14)	34.41 (16.44 to 44.32)

No statistical analyses for this end point

Secondary: Mitochondrial energy metabolism of unstimulated (ex vivo) CD8 T cells

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End point title

Mitochondrial energy metabolism of unstimulated (ex vivo) CD8 T cells ^[67]

End point description

Measurement of mitochondrial energy metabolism (i.e. oxidative phosphorylation) of unstimulated (ex vivo) CD8 T cells using seahorse agilent technology during DMF treatment.

End point type

Secondary

End point timeframe

Months 0, 6 and 11.

Notes
[67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	14
Units: oxygen consumption rate in pmol/min
median (inter-quartile range (Q1-Q3))
Month 0 (n = 14)	86.12 (60.22 to 132.35)
Month 6 (n = 14)	62.07 (36.14 to 81.76)
Month 11 (n = 14)	66.66 (34.79 to 121.96)

No statistical analyses for this end point

Secondary: Mitochondrial energy metabolism of short-term stimulated CD8 T cells

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End point title

Mitochondrial energy metabolism of short-term stimulated CD8 T cells ^[68]

End point description

Measurement of mitochondrial energy metabolism (i.e. oxidative phosphorylation) of short-term stimulated CD8 T cells using seahorse agilent technology during DMF treatment.

End point type

Secondary

End point timeframe

Months 0, 6 and 11.

Notes
[68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	14
Units: oxygen consumption rate in pmol/min
median (inter-quartile range (Q1-Q3))
Month 0 (n = 14)	34.90 (16.80 to 63.01)
Month 6 (n = 14)	19.99 (6.75 to 38.75)
Month 11 (n = 14)	21.90 (8.43 to 27.43)

No statistical analyses for this end point

Secondary: Migratory capacity of CD4 T cells

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End point title

Migratory capacity of CD4 T cells ^[69]

End point description

Migration analysis in an in vitro model of the blood-brain-barrier of unstimulated CD4 T cells during DMF treatment.

End point type

Secondary

End point timeframe

Months 0, 6 and 11.

Notes
[69] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	20
Units: Percentage of migrated cells
median (inter-quartile range (Q1-Q3))
Month 0 (n = 20)	19.77 (1.92 to 64.27)
Month 6 (n = 19)	19.64 (2.31 to 56.85)
Month 11 (n = 10)	1.66 (0.82 to 2.82)

No statistical analyses for this end point

Secondary: Migratory capacity of CD8 T cells

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End point title

Migratory capacity of CD8 T cells ^[70]

End point description

Migration analysis in an in vitro model of the blood-brain-barrier of unstimulated CD8 T cells during DMF treatment.

End point type

Secondary

End point timeframe

Months 0, 6 and 11.

Notes
[70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Because there were not enough samples from healthy subjects, this arm was not evaluated.

End point values	Dimethyl fumarate (DMF) (RRMS patients)
Number of subjects analysed	20
Units: Percentage of migrated cells
median (inter-quartile range (Q1-Q3))
Month 0 (n = 20)	11.50 (0.82 to 148.75)
Month 6 (n = 19)	19.44 (0.69 to 173.56)
Month 11 (n = 10)	0.83 (0.37 to 0.97)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From enrollment in the study to the final study visit.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Safety group

Reporting group description

RRMS patients who received at least one dose of dimethyl fumarate.

Serious adverse events	Safety group
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 42 (7.14%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Investigations
Weight decreased
subjects affected / exposed	1 / 42 (2.38%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0
Injury, poisoning and procedural complications
Radius fracture
subjects affected / exposed	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion
subjects affected / exposed	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Nervous system disorders
Cerebral ischaemia
subjects affected / exposed	1 / 42 (2.38%)
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 group
Total subjects affected by non serious adverse events
subjects affected / exposed	37 / 42 (88.10%)
Vascular disorders
Flushing
subjects affected / exposed	24 / 42 (57.14%)
occurrences all number	28
Hot flush
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	4 / 42 (9.52%)
occurrences all number	4
Feeling hot
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Oedema peripheral
subjects affected / exposed	2 / 42 (4.76%)
occurrences all number	2
Reproductive system and breast disorders
Menopausal symptoms
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Oropharyngeal pain
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Psychiatric disorders
Depression
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Aspartate aminotransferase increased
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Hepatic enzyme increased
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Protein urine present
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Injury, poisoning and procedural complications
Cartilage injury
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Foot fracture
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Cardiac disorders
Arrhythmia
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Tachycardia
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Nervous system disorders
Ataxia
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Dizziness
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Dysgeusia
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Headache
subjects affected / exposed	4 / 42 (9.52%)
occurrences all number	4
Hypertonia
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Hypoaesthesia
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Sensory loss
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Tremor
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Leukopenia
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Lymphopenia
subjects affected / exposed	3 / 42 (7.14%)
occurrences all number	3
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Eye disorders
Visual impairment
subjects affected / exposed	2 / 42 (4.76%)
occurrences all number	2
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Abdominal pain
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Abdominal pain upper
subjects affected / exposed	4 / 42 (9.52%)
occurrences all number	4
Aphthous ulcer
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Diarrhoea
subjects affected / exposed	5 / 42 (11.90%)
occurrences all number	6
Dry mouth
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Epigastric discomfort
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Flatulence
subjects affected / exposed	3 / 42 (7.14%)
occurrences all number	3
Gastric disorder
subjects affected / exposed	3 / 42 (7.14%)
occurrences all number	3
Gastrointestinal disorder
subjects affected / exposed	3 / 42 (7.14%)
occurrences all number	3
Nausea
subjects affected / exposed	4 / 42 (9.52%)
occurrences all number	4
Vomiting
subjects affected / exposed	2 / 42 (4.76%)
occurrences all number	2
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	4 / 42 (9.52%)
occurrences all number	7
Pruritus
subjects affected / exposed	6 / 42 (14.29%)
occurrences all number	7
Skin irritation
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Skin warm
subjects affected / exposed	2 / 42 (4.76%)
occurrences all number	2
Renal and urinary disorders
Proteinuria
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 42 (4.76%)
occurrences all number	2
Joint lock
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Muscular weakness
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Osteoarthritis
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Pain in extremity
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Infections and infestations
Acute sinusitis
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Bronchitis
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Folliculitis
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Gastric infection
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Gastroenteritis
subjects affected / exposed	2 / 42 (4.76%)
occurrences all number	2
Hand-foot-and-mouth disease
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Infection
subjects affected / exposed	2 / 42 (4.76%)
occurrences all number	2
Nasal herpes
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Nasopharyngitis
subjects affected / exposed	14 / 42 (33.33%)
occurrences all number	17
Oral herpes
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Rhinitis
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Tonsillitis
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1
Urinary tract infection
subjects affected / exposed	6 / 42 (14.29%)
occurrences all number	6
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 42 (2.38%)
occurrences all number	1

More information

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Were there any global substantial amendments to the protocol? Yes

06 Oct 2015

Inclusion and exclusion criteria of the protocol have been amended: • The time limit for disease-modifying treatment before the start of the trial was reduced from 6 months to one month (the procedure remained unchanged for patients who received IFN ß-1 or glatiramer acetate at the time of screening). • Previously, the test for tuberculosis, HIV and hepatitis B and C had to be performed during screening. After the amendment, test results not older than 3 months at the time of screening were also allowed. • Limit values for certain laboratory parameters have been removed. Only clinical significant deviations of the laboratory values lead to the exclusion of the patient (decision of the investigator). In addition, the following has been modified in the protocol: • In order to exclude pregnancy at the time of screening, a urine pregnancy test should now also be allowed (previously only a blood test was allowed). • The analysis of laboratory parameters (clinical chemistry) which are not recommended or obligatory according to the summary of product characteristics or the Krankheitsbezogenen Kompetenznetzes Multiple Sklerose should no longer be performed.

25 Apr 2017

Secondary objectives have been modified: • In order to examine the cytokine production of the cells, only the cytokines GM-CSF, IFNγ, TNF-α, IL-22 und IL-17A should be examined (the analysis of IL-2, IL-4, IL-10 and IL-21 was removed from the protocol). Secondary objectives have been removed: • Investigating the differentiation capability of T cells and the ability of regulatory T cells to suppress the effector T cell response were removed from the protocol. Secondary objectives have been added: • Evaluation of changes in mitochondrial energy metabolism was added to the protocol. Sample size / change to the power analyses: • Initially, it was planned to recruit 60 RRMS patients. Due to new external information concerning the mean change in Th17 cells, the number of RRMS patients was decreased to 50 patients and the power analysis was repeated.

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

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Clinical trials

Clinical Trial Results: A 24-week, multicenter, exploratory, two arm study to assess the effect of Dimethyl fumarate on Immune-Modulatory Action on T cells in patients with relapsing remitting Multiple Sclerosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of lymphocytes in PBMCs

Primary: Number of lymphocytes in PBMCs

Primary: Absolute change of lymphocytes in PBMCs

Primary: Absolute change of lymphocytes in PBMCs

Primary: Number of monocytes in PBMCs

Primary: Number of monocytes in PBMCs

Primary: Absolute change of monocytes in PBMCs

Primary: Absolute change of monocytes in PBMCs

Primary: Number of T cells in lymphocytes

Primary: Number of T cells in lymphocytes

Primary: Absolute change of T cells in lymphocytes

Primary: Absolute change of T cells in lymphocytes

Primary: Number of CD4 T cells in T cells

Primary: Number of CD4 T cells in T cells

Primary: Absolute change of CD4 T cells in T cells

Primary: Absolute change of CD4 T cells in T cells

Primary: Number of CD8 T cells in T cells

Primary: Number of CD8 T cells in T cells

Primary: Absolute change of CD8 T cells in T cells

Primary: Absolute change of CD8 T cells in T cells

Primary: Number of naive CD4 T cells in CD4 T cells

Primary: Number of naive CD4 T cells in CD4 T cells

Primary: Absolute change of naive CD4 T cells in CD4 T cells

Primary: Absolute change of naive CD4 T cells in CD4 T cells

Primary: Number of central memory CD4 T cells in CD4 T cells

Primary: Number of central memory CD4 T cells in CD4 T cells

Primary: Absolute change of central memory CD4 T cells in CD4 T cells

Primary: Absolute change of central memory CD4 T cells in CD4 T cells

Primary: Number of effector memory CD4 T cells in CD4 T cells

Primary: Number of effector memory CD4 T cells in CD4 T cells

Primary: Absolute change of effector memory CD4 T cells in CD4 T cells

Primary: Absolute change of effector memory CD4 T cells in CD4 T cells

Primary: Number of CD4 RTEs in CD4 T cells

Primary: Number of CD4 RTEs in CD4 T cells

Primary: Absolute change of CD4 RTEs in CD4 T cells

Primary: Absolute change of CD4 RTEs in CD4 T cells

Primary: Number of naive CD8 T cells in CD8 T cells

Primary: Number of naive CD8 T cells in CD8 T cells

Primary: Absolute change of naive CD8 T cells in CD8 T cells

Primary: Absolute change of naive CD8 T cells in CD8 T cells

Primary: Number of central memory CD8 T cells in CD8 T cells

Primary: Number of central memory CD8 T cells in CD8 T cells

Primary: Absolute change of central memory CD8 T cells in CD8 T cells

Primary: Absolute change of central memory CD8 T cells in CD8 T cells

Primary: Number of effector memory CD8 T cells in CD8 T cells

Primary: Number of effector memory CD8 T cells in CD8 T cells

Primary: Absolute change of effector memory CD8 T cells in CD8 T cells

Primary: Absolute change of effector memory CD8 T cells in CD8 T cells

Primary: Number of TEMRA in CD8 T cells

Primary: Number of TEMRA in CD8 T cells

Primary: Absolute change of TEMRA in CD8 T cells

Primary: Absolute change of TEMRA in CD8 T cells

Secondary: Number of GM-CSF-producing CD4 T cells

Secondary: Number of GM-CSF-producing CD4 T cells

Secondary: Absolute change of GM-CSF-producing CD4 T cells

Secondary: Absolute change of GM-CSF-producing CD4 T cells

Secondary: Number of IFN-gamma-producing CD4 T cells

Secondary: Number of IFN-gamma-producing CD4 T cells

Secondary: Absolute change of IFN-gamma-producing CD4 T cells

Secondary: Absolute change of IFN-gamma-producing CD4 T cells

Secondary: Number of IL-17A-producing CD4 T cells

Secondary: Number of IL-17A-producing CD4 T cells

Secondary: Absolute change of IL17A-producing CD4 T cells

Secondary: Absolute change of IL17A-producing CD4 T cells

Secondary: Number of IL-4-producing CD4 T cells

Secondary: Number of IL-4-producing CD4 T cells

Secondary: Absolute change of IL-4-producing CD4 T cells

Secondary: Absolute change of IL-4-producing CD4 T cells

Secondary: Absolute change of thymus derived regulatory T cells in memory CD4 T cells

Secondary: Absolute change of thymus derived regulatory T cells in memory CD4 T cells

Clinical Trial Results:
A 24-week, multicenter, exploratory, two arm study to assess the effect of Dimethyl fumarate on Immune-Modulatory Action on T cells in patients with relapsing remitting Multiple Sclerosis