Relapsing-Remitting Multiple Sclerosis
Conditions
Brief summary
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).
Detailed description
This study also includes a Diffusion Tensor Imaging (DTI) sub-study that includes healthy volunteers. Healthy volunteers will not receive any study medication.
Interventions
DRUGnatalizumab
Administered as specified in the treatment arm
DRUGfingolimod
Administered as specified in the treatment arm
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria for MS Patients: * Must have a documented diagnosis of relapsing MS (McDonald 2010 Criteria) at study screening with EDSS score from 0.0 to 5.5. * If the subject is on Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera, and Aubagio (BRACE-TA) at study screening: * He/she must have been on therapy for at least 6 months (unless experiencing highly active disease), have at least 9 T2-hyperintense lesions on a brain MRI scan, and have experienced ≥1 relapse within the last 6 months prior to study screening with ≥1 new T1-Gd+ lesion on a brain MRI scan performed ≤6 months prior to study screening or ≥2 new T2 lesions on a brain MRI scan performed ≤6 months prior to study screening, with comparison made to a T2 MRI scan performed up to 18 months before study screening * If the subject has highly active disease, regardless of whether they are disease-modifying therapy (DMT)-naïve or had previous exposure to Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera, and Aubagio (BRACE-TA), they must have had ≥2 disabling relapses in the 12 months prior to study screening and either ≥1 new T1-Gd+ lesion on a brain MRI scan performed ≤6 months prior to study screening or ≥2 new T2 lesions on a brain MRI scan performed ≤6 months prior to study screening, with comparison made to a T2 MRI scan performed up to 18 months before study screening Key
Exclusion criteria
for MS Patients: * Diagnosis of Primary Progressive Multiple Sclerosis and/or Secondary Progressive Multiple Sclerosis. * History or positive test result at study screening for human immunodeficiency virus (HIV), hepatitis C virus (HCV) antibody or current hepatitis B infection (defined as positive for hepatitis B surface antigen \[HBsAg\] and/or hepatitis B core antibody \[HBcAb\]). * Prior treatment with natalizumab or fingolimod. * History of or known active malignant disease, including solid tumors and hematologic malignancies (subjects with cutaneous basal and squamous cell carcinoma that has been completely excised and considered cured prior to study screening remain eligible). * History of opportunistic infections or any clinically significant major disease, as determined by the Investigator. * A clinically significant infectious illness (e.g., pneumonia, septicemia) within the 1 month prior to study screening. * History of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to study screening. * Prior history of immunosuppressant use (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate, cladribine, rituximab), or exposure to intravenous immunoglobulin (IGIV), monoclonal antibodies, cytokines, growth factors, soluble receptors, other recombinant products, or fusion proteins in the last 12 months prior to study screening. * History of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure in last 6 months. * Treatment with Class Ia (e.g., procainamide, quinidine, ajmaline, disopyramide) or Class III (amiodarone, bretylium, dofelitide, sotalol, ibulitide, azilimide) anti-arrhythmic drugs. * Concurrent therapy with drugs that slow heart rate (e.g., beta-blockers, heart-rate lowering calcium channel blockers such as diltiazem or verapamil, or digoxin). * Hypertension not controlled with prescribed medications. * History of severe respiratory disease, pulmonary fibrosis or class III or IV chronic obstructive pulmonary disease. * The use of live or live attenuated vaccination within 8 weeks of study screening. Key Inclusion Criteria for Healthy Volunteers: * Subjects who are generally healthy as demonstrated by physical examination and by medical history, with no history or evidence of major illnesses, diseases, or disorders. * Subjects of childbearing potential must practice effective contraception and be willing and able to continue contraception for duration of the study. * No history of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to study screening. Key
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cumulative Number of ≥ 6-Month Confirmed T1-Hypointense Lesions Arising From New On-Treatment T1-Gadolinium-Enhancing (Gd+) Lesions | Up to Week 52 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Risk of Relapse | Up to Week 52 | 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. |
| Cumulative Number of New T1-Gd+ Lesions | Baseline, Week 4, Week 12, Week 24 | — |
| Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24 | Baseline, Week 24 | As assessed by magnetic resonance imaging (MRI). |
| Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52 | Baseline, Week 52 | As assessed by MRI. |
| Time to First Relapse | Up to Week 52 | 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. |
| Proportion of Participants With No Evidence of Disease Activity (NEDA) | Up to Week 52 | 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. |
| Time to Complete Recovery From First Relapse | Up to Week 52 | 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. |
| Change From Baseline in Symbol Digit Modalities Test (SDMT) at Week 24 | Baseline, Week 24 | 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. |
| Change From Baseline in SDMT at Week 52 | Baseline, Week 52 | 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. |
| Cumulative Number of New or Enlarging T2 Lesions | Baseline, Week 24 | — |
Countries
Australia, Czechia, France, Germany, Italy, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 128 participants were screened, 111 participants were enrolled in the study. Three participants were not randomized and did not receive any dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Natalizumab Open-label natalizumab 300 mg IV every 4 weeks | 54 |
| Fingolimod Open-label fingolimod 0.5 mg once daily orally | 54 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Physician Decision | 0 | 3 |
| Overall Study | Sponsor Termination | 49 | 43 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Natalizumab | Fingolimod | Total |
|---|---|---|---|
| Age, Continuous | 38.19 years STANDARD_DEVIATION 8.811 | 34.87 years STANDARD_DEVIATION 8.731 | 36.53 years STANDARD_DEVIATION 8.887 |
| Sex: Female, Male Female | 37 Participants | 38 Participants | 75 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 54 | 23 / 54 |
| serious Total, serious adverse events | 0 / 54 | 2 / 54 |
Outcome results
Primary
Cumulative Number of ≥ 6-Month Confirmed T1-Hypointense Lesions Arising From New On-Treatment T1-Gadolinium-Enhancing (Gd+) Lesions
Time frame: Up to Week 52
Population: The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.
Secondary
Change From Baseline in SDMT at Week 52
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.
Time frame: Baseline, Week 52
Population: Intent-to-treat population: all randomized participants who received at least 1 dose of study treatment and had both baseline and post-baseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod | Change From Baseline in SDMT at Week 52 | 2.11 units on a scale | Standard Deviation 8.492 |
Secondary
Change From Baseline in Symbol Digit Modalities Test (SDMT) at Week 24
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.
Time frame: Baseline, Week 24
Population: Intent-to-treat population: all randomized participants who received at least 1 dose of study treatment and had both baseline and post-baseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Natalizumab | Change From Baseline in Symbol Digit Modalities Test (SDMT) at Week 24 | 3.79 units on a scale | Standard Deviation 8.684 |
| Fingolimod | Change From Baseline in Symbol Digit Modalities Test (SDMT) at Week 24 | 3.24 units on a scale | Standard Deviation 4.63 |
Secondary
Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24
As assessed by magnetic resonance imaging (MRI).
Time frame: Baseline, Week 24
Population: Intent-to-treat population: all randomized participants who received at least 1 dose of study treatment and had an assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Natalizumab | Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24 | T1 Lesion Volume Change | 0.5 percentage change | Standard Deviation 31.235 |
| Natalizumab | Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24 | T2 Lesion Volume Change | 0.08 percentage change | Standard Deviation 4.399 |
| Fingolimod | Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24 | T2 Lesion Volume Change | 3.32 percentage change | Standard Deviation 5.036 |
| Fingolimod | Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24 | T1 Lesion Volume Change | 1.81 percentage change | Standard Deviation 19.703 |
Comparison: T1 Lesion Volume Changep-value: 0.5318Wilcoxon rank-sum test
Comparison: T2 Lesion Volume Changep-value: 0.0528Wilcoxon rank-sum test
Secondary
Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52
As assessed by MRI.
Time frame: Baseline, Week 52
Population: Intent-to-treat population: all randomized participants who received at least 1 dose of study treatment and had an assessment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Fingolimod | Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52 | T1 Lesion Volume Change | -15.31 percentage change |
| Fingolimod | Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52 | T2 Lesion Volume Change | 5.6 percentage change |
Secondary
Cumulative Number of New or Enlarging T2 Lesions
Time frame: Baseline, Week 24
Population: Intent-to-treat population: all randomized participants who received at least 1 dose of study treatment and had an assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Natalizumab | Cumulative Number of New or Enlarging T2 Lesions | 1.33 lesions | Standard Deviation 2.469 |
| Fingolimod | Cumulative Number of New or Enlarging T2 Lesions | 1.94 lesions | Standard Deviation 2.205 |
p-value: 0.2632Wilcoxon rank-sum test
Secondary
Cumulative Number of New T1-Gd+ Lesions
Time frame: Baseline, Week 4, Week 12, Week 24
Population: Intent-to-treat population: all randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Natalizumab | Cumulative Number of New T1-Gd+ Lesions | From Baseline to Week 4 | 0.62 lesions | Standard Deviation 1.512 |
| Natalizumab | Cumulative Number of New T1-Gd+ Lesions | From Baseline to Week 12 | 0.68 lesions | Standard Deviation 1.695 |
| Natalizumab | Cumulative Number of New T1-Gd+ Lesions | From Baseline to Week 24 | 0.72 lesions | Standard Deviation 1.69 |
| Fingolimod | Cumulative Number of New T1-Gd+ Lesions | From Baseline to Week 4 | 1.69 lesions | Standard Deviation 4.122 |
| Fingolimod | Cumulative Number of New T1-Gd+ Lesions | From Baseline to Week 12 | 2.27 lesions | Standard Deviation 4.499 |
| Fingolimod | Cumulative Number of New T1-Gd+ Lesions | From Baseline to Week 24 | 2.6 lesions | Standard Deviation 4.745 |
Comparison: Week 4p-value: 0.126Wilcoxon rank-sum test
Comparison: Week 4p-value: 0.3525negative binomial regression
Comparison: Week 12p-value: 0.0127Wilcoxon rank-sum test
Comparison: Week 12p-value: 0.0299negative binomial regression
Comparison: Week 24p-value: 0.0123Wilcoxon rank-sum test
Comparison: Week 24p-value: 0.0076negative binomial regression
Secondary
Cumulative Risk of Relapse
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.
Time frame: Up to Week 52
Population: The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.
Secondary
Proportion of Participants With No Evidence of Disease Activity (NEDA)
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.
Time frame: Up to Week 52
Population: The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.
Secondary
Time to Complete Recovery From First Relapse
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.
Time frame: Up to Week 52
Population: The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.
Secondary
Time to First Relapse
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.
Time frame: Up to Week 52
Population: The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.