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
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EudraCT number |
2014-003481-25 |
Trial protocol |
DE |
Global end of trial date |
07 May 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Jan 2020
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First version publication date |
04 Jan 2020
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
DIMAT-MS
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
U1111-1164-2476 | ||
Sponsors
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Sponsor organisation name |
Universitätsklinikum Münster
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Sponsor organisation address |
Albert-Schweitzer-Campus 1, Gebäude D5, Münster, Germany, 48149
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Public contact |
Klinik für Allgemeine Neurologie, Universitätsklinikum Münster, Luisa.Klotz@ukmuenster.de
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Scientific contact |
Klinik für Allgemeine Neurologie, Universitätsklinikum Münster, Luisa.Klotz@ukmuenster.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
07 May 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 May 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
07 May 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 67
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Worldwide total number of subjects |
67
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EEA total number of subjects |
67
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
67
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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. | |||||||||||||||||||||||||||||||||
Pre-assignment
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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. | |||||||||||||||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
67 | |||||||||||||||||||||||||||||||||
Number of subjects completed |
58 | |||||||||||||||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Not meeting inclusion criteria: 8 | |||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Consent withdrawn by subject: 1 | |||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dimethyl fumarate (DMF) (RRMS patients) | |||||||||||||||||||||||||||||||||
Arm description |
RRMS patients treated with dimethyl fumarate. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Tecfidera
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Investigational medicinal product code |
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Other name |
Dimethyl fumarate
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Pharmaceutical forms |
Gastro-resistant capsule, hard
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Routes of administration |
Oral use
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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).
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Arm title
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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
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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. |
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Baseline characteristics reporting groups
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Reporting group title |
Dimethyl fumarate (DMF) (RRMS patients)
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Reporting group description |
RRMS patients treated with dimethyl fumarate. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
No treatment (Healthy subjects)
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Reporting group description |
Healthy subjects who have not been treated. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Dimethyl fumarate (DMF) (RRMS patients)
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Reporting group description |
RRMS patients treated with dimethyl fumarate. | ||
Reporting group title |
No treatment (Healthy subjects)
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Reporting group description |
Healthy subjects who have not been treated. |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
Months 0, 2, 4, 6 and 11.
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
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. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
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. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
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. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
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. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
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. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
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. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From enrollment in the study to the final study visit.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
Safety group
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Reporting group description |
RRMS patients who received at least one dose of dimethyl fumarate. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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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. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |