Secondary-progressive Multiple Sclerosis
Conditions
Brief summary
To assess the efficacy of Mayzent on microglia pathology in patients with active SPMS, as compared to the active control group of MS patients treated with the Ocrevus, as measured by changes in microglial activation in the lesional and non-lesional NAWM and NAGM and in the peri-plaque area of chronic lesions in the brain.
Detailed description
Multiple sclerosis (MS) is primarily a demyelinating disease of the central nervous system (CNS), but many patients also undergo progressive atrophy, especially in the gray matter (GM). GM atrophy plays a particularly prominent role in development of cognitive and physical disability in MS. Evidence is mounting that there is a profound infiltration of activated microglia and blood-borne macrophages throughout the lesions, whereas in slowly expanding (smoldering) or chronic active expanding lesions, the microglia and macrophages are concentrated as a dense rim around the lesions. Microglia is also activated, in a more diffuse way, in the white matter (WM) and GM with concomitant axonal degeneration and meningeal inflammation. Thus, chronic activation of microglia has been linked to neurodegeneration in the progressive phase of the disease and development of brain atrophy. No longitudinal studies in MS examined the association between development of microglia-related pathology in patients treated with siponimod (Mayzent®). This will be the first study to examine the treatment effect of Mayzent on microglia in MS.
Interventions
Sponsors
State University of New York at Buffalo
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
SINGLE (Outcomes Assessor)
Masking description
Analysts had no knowledge of study drug assignment. .
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Patients diagnosed with active SPMS according to the Lublin 2014 criteria. Activity is determined by MRI activity (contrast-enhancing lesions; new and unequivocally enlarging T2 lesions) and/or clinical relapses in the 24 months prior to the study baseline. If the clinical MRI is not available to determine the activity (contrast-enhancing lesions; new and unequivocally enlarging T2 lesions), then a screening MRI will be offered to the subjects to determine inclusion/
Exclusion criteria
eligibility. * Age between 18 and 60 years * Have EDSS scores between 3.0 and 6.5 * Treatment naïve to both Mayzent and to Ocrevus * Not being on S1P modulators or B-cell therapies for the last 9 months * Subjects starting treatment as part of their clinical routine * Be willing and able to comply with the study procedures for the duration of the trial * Have given written informed consent and signed Health Insurance Portability and Accountability Act (HIPAA) authorization before any study-related activities are carried out * Normal kidney functioning (creatinine clearance \>59) * No known hypersensitivity reactions to contrast agents * None of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in PET Activation at 12 Months | 12 months | Change from baseline in PET activation of PBR06 in lesional and non-lesional NAWM and NAGM in the brain of the patients under treatment with Mayzent when 100% of patients reach 12 months; |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in PET Activation at 6,12,24 and 36 Months Between Mayzent and Active Comparator | 6, 12, 24 and 36 months | Change from baseline in PET activation of PBR06 in lesional and non-lesional NAWM and NAGM in the brain of the patients treated with Mayzent and active control group at 6, 12, 24 and 36 months from baseline |
| Number of New Ultrasmall Superparamagnetic Iron Oxide Particles | 6, 12, 24 and 36 months | The cumulative number of new ultrasmall superparamagnetic iron oxide (USPIO) particles contrast enhancing (CE) active lesions on T1-weighted images between Mayzent and active control group, as measured at 6, 12, 24 and 36 months from baseline. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Related Adverse Events | 12, 24, and 36 months | Safety of Mayzent and active control group over 12, 24, and 36 months of the study |
| MRI Measures Between Mayzent and Control-treated Groups (PBVC) | 12, 24 and 36 months | Percent brain volume change (PBVC) between baseline and 12, 24, and 36 months |
| MRI Measures Between Mayzent and Control-treated Groups (PCVC) | 12, 24 and 36 months | Percent cortical volume change (PCVC), between baseline and 12, 24, and 36 months |
| MRI Measures Between Mayzent and Control-treated Groups(PTVC) | 12, 24 and 36 months | Percent thalamus volume change (PTVC) between baseline and 12, 24, and 36 months |
| Absolute Change in Hypo-intense T1 Lesions Volume | 6, 12, 24 and 36 months | The absolute change in hypo-intense T1-lesion volume (LV) measured at months 6, 12, 24 and 36 months |
| Cumulative Number of New Gadolinium CE Lesions | 6, 12, 24 and 36 months | The cumulative number of new gadolinium CE lesions on T1-weighted images at months 6, 12, 24 and 36 months |
| Cumulative Number of New or Newly Enlarging T2 Lesions | 6, 12, 24 and 36 months | The cumulative number of new or newly enlarging hyperintense T2 lesions measured at months 6, 12, 24 and 36 months |
| Absolute Change in Hyperintense T2 Lesions Volume | 6, 12, 24 and 36 months | The absolute change in hyperintense T2-lesion volume (LV) measured at months 6, 12, 24 and 36 months |
| MRI Measures Between Mayzent and Control-treated Groups (QSM) | 12, 24 and 36 months | Quantitative susceptibility mapp (QSM) change between baseline and 12, 24, and 36 months |
| Absolute Change in Serum Neurofilament and Glial Protein | 6, 12, 24 and 36 months | The absolute change in serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (GFAP) at 6, 12, 24 and 36 months |
| Association Between Imaging and Clinical and Cognitive Outcomes | 24 and 36 months | The association between imaging and clinical and cognitive outcomes, incl. the composite EDSS+SDMT, over 24 and 36 months of the study |
Countries
United States
Participant flow
Recruitment details
Patients diagnosed with active SPMS according to the Lublin 2014 criteria. Activity is determined by MRI activity (contrast-enhancing lesions; new and unequivocally enlarging T2 lesions) and/or clinical relapses in the 24 months prior to the study baseline. Patients were recruited from 2 medical clinics.
Participants by arm
| Arm | Count |
|---|---|
| Ocrevus Patients diagnosed with secondary-progressive multiple sclerosis who have been prescribed Ocrevus by their neurologist.
Ocrevus: PET imaging to evaluate the effects of Ocrevus on the microglia of the brain. | 5 |
| Mayzent Patients diagnosed with secondary-progressive multiple sclerosis who have been prescribed Mayzent by their neurologist.
Mayzent: PET imaging to evaluate the effects of Mayzent on the microglia of the brain. | 3 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study closed | 5 | 3 |
Baseline characteristics
| Characteristic | Ocrevus | Mayzent | Total |
|---|---|---|---|
| Age, Continuous | 51 years | 53 years | 52 years |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 3 |
| other Total, other adverse events | 0 / 5 | 2 / 3 |
| serious Total, serious adverse events | 0 / 5 | 0 / 3 |
Outcome results
Primary
Change From Baseline in PET Activation at 12 Months
Change from baseline in PET activation of PBR06 in lesional and non-lesional NAWM and NAGM in the brain of the patients under treatment with Mayzent when 100% of patients reach 12 months;
Time frame: 12 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Secondary
Change From Baseline in PET Activation at 6,12,24 and 36 Months Between Mayzent and Active Comparator
Change from baseline in PET activation of PBR06 in lesional and non-lesional NAWM and NAGM in the brain of the patients treated with Mayzent and active control group at 6, 12, 24 and 36 months from baseline
Time frame: 6, 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Secondary
Number of New Ultrasmall Superparamagnetic Iron Oxide Particles
The cumulative number of new ultrasmall superparamagnetic iron oxide (USPIO) particles contrast enhancing (CE) active lesions on T1-weighted images between Mayzent and active control group, as measured at 6, 12, 24 and 36 months from baseline.
Time frame: 6, 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
Absolute Change in Hyperintense T2 Lesions Volume
The absolute change in hyperintense T2-lesion volume (LV) measured at months 6, 12, 24 and 36 months
Time frame: 6, 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
Absolute Change in Hypo-intense T1 Lesions Volume
The absolute change in hypo-intense T1-lesion volume (LV) measured at months 6, 12, 24 and 36 months
Time frame: 6, 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
Absolute Change in Serum Neurofilament and Glial Protein
The absolute change in serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (GFAP) at 6, 12, 24 and 36 months
Time frame: 6, 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
Association Between Imaging and Clinical and Cognitive Outcomes
The association between imaging and clinical and cognitive outcomes, incl. the composite EDSS+SDMT, over 24 and 36 months of the study
Time frame: 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
Cumulative Number of New Gadolinium CE Lesions
The cumulative number of new gadolinium CE lesions on T1-weighted images at months 6, 12, 24 and 36 months
Time frame: 6, 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
Cumulative Number of New or Newly Enlarging T2 Lesions
The cumulative number of new or newly enlarging hyperintense T2 lesions measured at months 6, 12, 24 and 36 months
Time frame: 6, 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
MRI Measures Between Mayzent and Control-treated Groups (PBVC)
Percent brain volume change (PBVC) between baseline and 12, 24, and 36 months
Time frame: 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
MRI Measures Between Mayzent and Control-treated Groups (PCVC)
Percent cortical volume change (PCVC), between baseline and 12, 24, and 36 months
Time frame: 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
MRI Measures Between Mayzent and Control-treated Groups(PTVC)
Percent thalamus volume change (PTVC) between baseline and 12, 24, and 36 months
Time frame: 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
MRI Measures Between Mayzent and Control-treated Groups (QSM)
Quantitative susceptibility mapp (QSM) change between baseline and 12, 24, and 36 months
Time frame: 12, 24 and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.
Other Pre-specified
Number of Participants With Treatment Related Adverse Events
Safety of Mayzent and active control group over 12, 24, and 36 months of the study
Time frame: 12, 24, and 36 months
Population: Study was terminated. No subject had any further data collected after the initial visit.