Multiple Sclerosis (MS)
Conditions
Keywords
Radiologically Isolated Syndrome (RIS)
Brief summary
The purpose of this investigation is to systematically study the efficacy of Tecfidera in those individuals who possess incidental white matter anomalies within the brain following a MRI study that is performed for a reason other than for the evaluation of MS (multiple sclerosis).
Detailed description
This is a multi-center, randomized, double-blinded study in which approximately 90 RIS (radiologically isolated syndrome) subjects will be treated with either Tecfidera or placebo for 2 years (1:1 randomization). Study participants, along with the treating and examining physicians, will be blinded to treatment assignment. Central Clinical and Imaging Units will screen all potential study subjects for inclusion/exclusion criteria. We expect to enroll all RIS subjects within the U.S. Following informed consent and verification of entry criteria by the core units, study participants will be randomized 1:1 to either Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) or placebo. Clinical follow-up by the treating physician will occur at weeks 0, 48, 96, 144 and/or End of Study and during or immediately following clinical exacerbations. During clinical visits, comprehensive medical history data will be obtained by the treating physician. All reported acute or progressive clinical events will be adjudicated by the Central Clinical Unit. Clinical visits due to suspected exacerbations associated with CNS (central nervous system) demyelination, and associated diagnostic studies and treatments, will be covered under the medical standard of care by third party payers. A recommendation to re-evaluate the patient within 3 months following the clinical event to assess for extent of recovery will be made. In addition to the face-to-face visits described above, study participants will be contacted over the telephone at weeks 4, 8, 36, 60, 84, 108, and 132 to assess for medical or treatment difficulties and for study medication compliance. Standardized MRI studies of the brain will be performed at weeks 0, 96, 144 or End of Study. Clinical imaging studies of the brain and/or spinal cord performed during or immediately following the onset of a clinical exacerbation will be performed at the discretion of the site PI with scan costs covered under the medical standard of care. An end of study clinical MRI of the cervical spinal cord with and without contrast will be recommended to study participants at week 96 as medical standard of care.
Interventions
DRUGTecfidera
Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs.
DRUGPlacebo
Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs.
Sponsors
Biogen
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females meeting 2009 RIS criteria 2. Identified RIS cases with the initial MRI demonstrating anomalies suggestive of demyelinating disease dated \> 2009 3. Incidental anomalies identified on MRI of the brain or spinal cord with the primary reason for the acquired MRI resulting from an evaluation of a process other than MS 4. CNS white matter anomalies meeting the following MRI criteria: * Ovoid, well-circumscribed, and homogeneous foci with or without involvement of the corpus callosum * T2-hyperintensities measuring \> 3mm2 and fulfilling 3 of 4 Barkhof-Tintoré criteria for dissemination in space * CNS anomalies not consistent with a vascular pattern * Qualitative determination that CNS anomalies have a characteristic appearance of demyelinating lesions 5. MRI anomalies do not account for clinically apparent neurological impairments in patients
Exclusion criteria
1. Women who are pregnant or nursing 2. Incomplete medical history or radiological data 3. History of remitting clinical symptoms consistent with multiple sclerosis lasting \> 24 hours prior to CNS imaging revealing anomalies suggestive of MS 4. History of paroxysmal symptoms associated with MS (i.e. Lhermitte's or Uhthoff's phenomena) 5. CNS MRI anomalies are better accounted for by another disease process 6. The subject is unwilling or unable to comply with the requirements of the study protocol 7. Exposure to a disease modifying therapy for MS/RIS within the past 3 months 8. Exposure to high-dose glucocorticosteroid treatment within the past 30 days 9. Participation in other clinical trials involving treatment with a disease-modifying agent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Time From Randomization to the First Demyelinating Event (Acute or Development of an Initial Symptom Resulting in a Progressive Clinical Course) | 96 weeks | The primary outcome measure for this trial is the time to the first acute or progressive neurological event resulting from CNS demyelination from randomization into the trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of New T2 Lesions | 96 weeks | Number of new T2 lesions as measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. |
| Change in Lesion Volume on T2-weighted MRI | Baseline, 96 weeks | Change in lesion volume on T2-weighted MRI is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. |
| Number of Newly Enlarging T2 Lesions | 96 weeks | Number of newly enlarging T2 lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. |
| Number of Contrast Enhancing Lesions | 96 weeks | Number of contrast enhancing lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. |
| Change in the Number of Participants With Brain Atrophy | Baseline, 96 weeks | Change in the number of participants with brain atrophy is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. |
| Newly Enlarging T2 Lesions and New T2 Lesions Combined | 96 weeks | Newly enlarging T2 lesions and new T2 lesions combined is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tecfidera Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily)
Tecfidera: Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. | 44 |
| Placebo Placebo by mouth twice daily.
Placebo: Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs. | 43 |
| Total | 87 |
Baseline characteristics
| Characteristic | Placebo | Tecfidera | Total |
|---|---|---|---|
| Age, Continuous | 44.81 years STANDARD_DEVIATION 13.88 | 43.57 years STANDARD_DEVIATION 12.87 | 44.18 years STANDARD_DEVIATION 13.32 |
| Expanded Disability Status Scale (EDSS) | 1 units on a scale | 1 units on a scale | 1 units on a scale |
| Multiple Sclerosis (MS) family history | 6 Participants | 3 Participants | 9 Participants |
| Presence of gadolinium enhancing lesions | 2 Participants | 6 Participants | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 38 Participants | 40 Participants | 78 Participants |
| Sex: Female, Male Female | 30 Participants | 31 Participants | 61 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 26 Participants |
| T2-weighted hyperintense lesion volume | 7.32 mm^3 STANDARD_DEVIATION 0.89 | 7.30 mm^3 STANDARD_DEVIATION 1.07 | 7.31 mm^3 STANDARD_DEVIATION 0.97 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 43 |
| other Total, other adverse events | 44 / 44 | 43 / 43 |
| serious Total, serious adverse events | 4 / 44 | 4 / 43 |
Outcome results
Primary
The Time From Randomization to the First Demyelinating Event (Acute or Development of an Initial Symptom Resulting in a Progressive Clinical Course)
The primary outcome measure for this trial is the time to the first acute or progressive neurological event resulting from CNS demyelination from randomization into the trial.
Time frame: 96 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tecfidera | The Time From Randomization to the First Demyelinating Event (Acute or Development of an Initial Symptom Resulting in a Progressive Clinical Course) | 89.69 weeks | Standard Deviation 23.99 |
| Placebo | The Time From Randomization to the First Demyelinating Event (Acute or Development of an Initial Symptom Resulting in a Progressive Clinical Course) | 77.81 weeks | Standard Deviation 32.19 |
Secondary
Change in Lesion Volume on T2-weighted MRI
Change in lesion volume on T2-weighted MRI is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
Time frame: Baseline, 96 weeks
Population: 3 participants out of 30 who completed the assigned treatment, their baseline MRI data was missing and hence were not analyzed.~3 participants out of 29 who completed the assigned placebo arm, their MRI data was not collected due to technical issues and hence were not analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tecfidera | Change in Lesion Volume on T2-weighted MRI | 0.005 mm³ | Standard Deviation 0.03 |
| Placebo | Change in Lesion Volume on T2-weighted MRI | 0.04 mm³ | Standard Deviation 0.03 |
Secondary
Change in the Number of Participants With Brain Atrophy
Change in the number of participants with brain atrophy is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
Time frame: Baseline, 96 weeks
Population: Data were not collected.
Secondary
Newly Enlarging T2 Lesions and New T2 Lesions Combined
Newly enlarging T2 lesions and new T2 lesions combined is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
Time frame: 96 weeks
Population: 3 participants out of 30 who completed the assigned treatment, their baseline MRI data was missing and hence were not analyzed.~3 participants out of 29 who completed the assigned placebo arm, their MRI data was not collected due to technical issues and hence were not analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tecfidera | Newly Enlarging T2 Lesions and New T2 Lesions Combined | 0.12 T2 lesions | Standard Deviation 0.07 |
| Placebo | Newly Enlarging T2 Lesions and New T2 Lesions Combined | 0.62 T2 lesions | Standard Deviation 0.3 |
Secondary
Number of Contrast Enhancing Lesions
Number of contrast enhancing lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
Time frame: 96 weeks
Population: 3 participants out of 30 who completed the assigned treatment, their baseline MRI data was missing and hence were not analyzed.~3 participants out of 29 who completed the assigned placebo arm, their MRI data was not collected due to technical issues and hence were not analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tecfidera | Number of Contrast Enhancing Lesions | 0.07 contrast enhancing lesions | Standard Deviation 0.38 |
| Placebo | Number of Contrast Enhancing Lesions | 0 contrast enhancing lesions | Standard Deviation 0 |
Secondary
Number of Newly Enlarging T2 Lesions
Number of newly enlarging T2 lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
Time frame: 96 weeks
Population: 3 participants out of 30 who completed the assigned treatment, their baseline MRI data was missing and hence were not analyzed.~3 participants out of 29 who completed the assigned placebo arm, their MRI data was not collected due to technical issues and hence were not analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tecfidera | Number of Newly Enlarging T2 Lesions | 0.03 T2 lesions | Standard Deviation 0.003 |
| Placebo | Number of Newly Enlarging T2 Lesions | 0.10 T2 lesions | Standard Deviation 0.07 |
Secondary
Number of New T2 Lesions
Number of new T2 lesions as measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group.
Time frame: 96 weeks
Population: 3 participants out of 30 who completed the assigned treatment, their baseline MRI data was missing and hence were not analyzed.~3 participants out of 29 who completed the assigned placebo arm, their MRI data was not collected due to technical issues and hence were not analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tecfidera | Number of New T2 Lesions | 0.09 T2 lesions | Standard Deviation 0.06 |
| Placebo | Number of New T2 Lesions | 0.54 T2 lesions | Standard Deviation 0.28 |