Clinical Trial Results:
A Multicenter, Randomized, Open-Label Study to Assess the Impact of Natalizumab versus Fingolimod on Central Nervous System Tissue Damage and Recovery in Active Relapsing-Remitting Multiple Sclerosis Subjects
Summary
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EudraCT number |
2013-004622-29 |
Trial protocol |
IT CZ GB SE ES DE DK |
Global end of trial date |
17 May 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Jun 2017
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First version publication date |
02 Jun 2017
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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 |
101MS408
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02342704 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Biogen
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Sponsor organisation address |
225 Binney Street,, Cambridge, Massachusetts, United States, 02142
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Public contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
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Scientific contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
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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 |
17 May 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
17 May 2016
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to assess the effect of natalizumab compared to fingolimod on the evolution of new on-treatment T1-gadolinium-enhancing (Gd+) lesions to persistent black holes (PBH) over 52 weeks. The secondary objectives of this study in this study population are to assess the effect of natalizumab compared to fingolimod on: magnetic resonance imaging (MRI) measures of central nervous system (CNS) tissue destruction as measured by the number of new T1-Gd+ lesions; various other MRI measures of disease activity; No Evidence of Disease Activity (NEDA); Relapse on treatment over 52 weeks; The change in information processing speed as measured by the Symbol Digit Modalities Test (SDMT).
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Protection of trial subjects |
Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Nov 2014
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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 |
Spain: 21
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Country: Number of subjects enrolled |
Sweden: 5
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
United States: 28
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Country: Number of subjects enrolled |
Australia: 3
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Country: Number of subjects enrolled |
Czech Republic: 40
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
Italy: 4
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Worldwide total number of subjects |
111
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EEA total number of subjects |
80
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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) |
111
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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 |
- | ||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
128 subjects were screened for this study, and 111 were enrolled. Three subjects were not randomized and did not receive any dose of study drug. | ||||||||||||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
111 | ||||||||||||||||||||||||||||||
Number of subjects completed |
108 | ||||||||||||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Enrolled, not randomized: 3 | ||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
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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Natalizumab | ||||||||||||||||||||||||||||||
Arm description |
Open-label natalizumab 300 mg IV every 4 weeks | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
natalizumab
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Investigational medicinal product code |
BG00002
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Other name |
Tysabri
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Pharmaceutical forms |
Concentrate and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects randomly assigned to the natalizumab group were to receive open-label natalizumab 300 mg IV infused over a 1-hour period (or per local label) every 4 weeks with the last dose planned for administration at Week 52.
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Arm title
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Fingolimod | ||||||||||||||||||||||||||||||
Arm description |
Open-label fingolimod 0.5 mg once daily orally | ||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
fingolimod
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Investigational medicinal product code |
FTY720
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Other name |
Gilenya
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects randomly assigned to the fingolimod group were to receive open-label fingolimod 0.5 mg orally once daily with the last dose planned to be administered at Week 52. Subjects were instructed to take their oral medication at the same time each day.
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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: 111 subjects were enrolled. Three subjects were not randomized and did not receive any dose of study drug. |
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Baseline characteristics reporting groups
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Reporting group title |
Natalizumab
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Reporting group description |
Open-label natalizumab 300 mg IV every 4 weeks | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fingolimod
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Reporting group description |
Open-label fingolimod 0.5 mg once daily orally | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Natalizumab
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Reporting group description |
Open-label natalizumab 300 mg IV every 4 weeks | ||
Reporting group title |
Fingolimod
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Reporting group description |
Open-label fingolimod 0.5 mg once daily orally |
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End point title |
Cumulative Number of ≥ 6-Month Confirmed T1-Hypointense Lesions Arising From New On-Treatment T1-Gadolinium-ENhancing (Gd+) Lesions [1] | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Up to Week 52
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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: Descriptive statistics are presented, per protocol. |
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Notes [2] - Due to lack of data, this analysis was not done. [3] - Due to lack of data, this analysis was not done. |
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No statistical analyses for this end point |
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End point title |
Cumulative Number of New T1-Gd+ Lesions | |||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Week 4, Week 12, Week 24
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Statistical analysis title |
Statistical Analysis 1 | |||||||||||||||||||||
Statistical analysis description |
Week 4
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Comparison groups |
Natalizumab v Fingolimod
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Number of subjects included in analysis |
92
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.126 | |||||||||||||||||||||
Method |
Wilcoxon rank-sum test | |||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 2 | |||||||||||||||||||||
Statistical analysis description |
Week 4
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Comparison groups |
Natalizumab v Fingolimod
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Number of subjects included in analysis |
92
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.3525 | |||||||||||||||||||||
Method |
negative binomial regression | |||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statisical Analysis 3 | |||||||||||||||||||||
Statistical analysis description |
Week 12
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Comparison groups |
Natalizumab v Fingolimod
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Number of subjects included in analysis |
92
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0127 | |||||||||||||||||||||
Method |
Wilcoxon rank-sum test | |||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 4 | |||||||||||||||||||||
Statistical analysis description |
Week 12
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Comparison groups |
Natalizumab v Fingolimod
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Number of subjects included in analysis |
92
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0299 | |||||||||||||||||||||
Method |
negative binomial regression | |||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 5 | |||||||||||||||||||||
Statistical analysis description |
Week 24
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Comparison groups |
Natalizumab v Fingolimod
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Number of subjects included in analysis |
92
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0123 | |||||||||||||||||||||
Method |
Wilcoxon rank-sum test | |||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 6 | |||||||||||||||||||||
Statistical analysis description |
Week 24
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Comparison groups |
Natalizumab v Fingolimod
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Number of subjects included in analysis |
92
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||
P-value |
= 0.0076 | |||||||||||||||||||||
Method |
negative binomial regression | |||||||||||||||||||||
Confidence interval |
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End point title |
Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24 | ||||||||||||||||||
End point description |
As assessed by magnetic resonance imaging (MRI).
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||
Statistical analysis description |
T1 Lesion Volume Change
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Comparison groups |
Natalizumab v Fingolimod
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Number of subjects included in analysis |
31
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.5318 | ||||||||||||||||||
Method |
Wilcoxon rank-sum test | ||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||
Statistical analysis description |
T2 Lesion Volume Change
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Comparison groups |
Natalizumab v Fingolimod
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Number of subjects included in analysis |
31
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.0528 | ||||||||||||||||||
Method |
Wilcoxon rank-sum test | ||||||||||||||||||
Confidence interval |
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End point title |
Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52 | ||||||||||||||||||
End point description |
As assessed by MRI.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52
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Notes [4] - No subjects were evaluated at this time point. [5] - 99999=not applicable; only 1 subject was evaluated. |
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No statistical analyses for this end point |
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End point title |
Cumulative Number of New or Enlarging T2 Lesions | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Natalizumab v Fingolimod
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Number of subjects included in analysis |
31
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.2632 | ||||||||||||
Method |
Wilcoxon rank-sum test | ||||||||||||
Confidence interval |
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End point title |
Proportion of Subjects With No Evidence of Disease Activity (NEDA) | |||||||||
End point description |
NEDA was defined as all of the following: no relapses; no 12-week confirmed disability progression based on Expanded Disability Status Scale (EDSS; defined as an increase of 1.0 or more on the EDSS from baseline of 1.0 or more, or an increase of 1.5 or more from a baseline score of 0) that was sustained for 12 weeks; no new T1-Gd+ lesions on brain MRI. No new or enlarging T2-hyperintense lesions.
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End point type |
Secondary
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End point timeframe |
Up to Week 52
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Notes [6] - Due to lack of data, this analysis was not done. [7] - Due to lack of data, this analysis was not done. |
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No statistical analyses for this end point |
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End point title |
Time to First Relapse | |||||||||
End point description |
A clinical relapse was defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement.
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End point type |
Secondary
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End point timeframe |
Up to Week 52
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Notes [8] - Due to lack of data, this analysis was not done. [9] - Due to lack of data, this analysis was not done. |
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No statistical analyses for this end point |
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End point title |
Cumulative Risk of Relapse | |||||||||
End point description |
A clinical relapse was defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement.
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End point type |
Secondary
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End point timeframe |
Up to Week 52
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Notes [10] - Due to lack of data, this analysis was not done. [11] - Due to lack of data, this analysis was not done. |
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No statistical analyses for this end point |
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End point title |
Time to Complete Recovery From First Relapse | |||||||||
End point description |
12-week confirmed complete EDSS recovery from first on-treatment relapse is defined as an EDSS score that is equal to or lower than the last pre-relapse EDSS score and sustained for at least 12 weeks.
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End point type |
Secondary
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End point timeframe |
Up to Week 52
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Notes [12] - Due to lack of data, this analysis was not done. [13] - Due to lack of data, this analysis was not done. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Symbol Digit Modalities Test (SDMT) at Week 24 | ||||||||||||
End point description |
The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements of attention, visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items from 0-110 in 90 seconds. The total score provides a measure of the speed and accuracy of symbol-digit substitution.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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No statistical analyses for this end point |
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End point title |
Change From Baseline in SDMT at Week 52 | ||||||||||||
End point description |
The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements of attention, visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items from 0-110 in 90 seconds. The total score provides a measure of the speed and accuracy of symbol-digit substitution.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52
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Notes [14] - No subjects were evaluated at this time point. |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Up to 64 weeks.
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Adverse event reporting additional description |
Treatment-emergent adverse events are presented.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Natalizumab
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Reporting group description |
Open-label natalizumab 300 mg IV every 4 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fingolimod
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Reporting group description |
Open-label fingolimod 0.5 mg once daily orally | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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10 Jul 2014 |
- A tertiary endpoint for atrophy was revised and a tertiary endpoint for magnetization transfer ratio (MTR) was added.
- “Freedom from Measured Disease Activity” was replaced with “No Evidence of Disease Activity”.
- The “abstinence” description under contraceptives was revised with language consistent with the Medicines and Healthcare Products Regulatory Agency.
-The definition of End of Study was revised to be consistent with other similar protocols. |
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13 Oct 2014 |
- The number of study visits during which study assessments were collected was decreased for subjects with MS. - Inclusion criteria were revised such that subjects on certain therapies at study screening were required to have at least 9 T2-hyperintense lesions on a brain MRI scan instead of 2 T2-hyperintense lesions, and subjects who were DMT naïve at study screening must have had at least 2 disabling relapses within 1 year prior to study screening instead of 2 unspecified relapses. - Exclusion criteria for subjects with relapsing MS were expanded. Additional criteria were added to exclude a history of congenital QT prolongation and unexplained hypokalemia, and any current therapy with drugs that prolong the corrected QT interval or are potent inducers of CYP450. - Exclusion criteria for subjects with MS were expanded; exclusion criteria for healthy volunteers were expanded. - Absolute lymphocyte count was added to the list of hematology assessments. - Treatment precautions with fingolimod were expanded. - Disallowed concomitant therapy was expanded; cautionary text was added for concomitant administration of certain therapies in patients with relevant risk factors. - Hematology assessments at certain weeks were eliminated. - Blood chemistry assessments at certain weeks were eliminated for natalizumab subjects but retained for fingolimod subjects; an additional blood chemistry assessment was added at Week 4 for fingolimod subjects. - Urinalysis assessments were eliminated for all subjects. - Pulmonary function test at Screening was revised. - Vital sign assessments for fingolimod subjects were eliminated from certain weeks. - Discontinuation of study treatment was expanded to include MS subjects who developed any contraindications to fingolimod and natalizumab, as well as any medical conditions described in the warnings and precautions of the 2 study treatments that made the subject unsuitable for study participation in the opinion of the Investigator. |
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01 May 2015 |
- Clarification of the requirements in inclusion criteria #5 and #6 to expand the list of permitted prior DMTs
- Reduction of the time required for a subject to be on a DMT at screening
- Inclusion of potential subjects who had highly-active disease. |
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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 |