Silent Progression Activity Monitoring - SPAM Study

Study Overview
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Brief Summary
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Real-World Data (RWD) exploring the natural history of MS suggested that relapses do not significantly influence the progression of irreversible disability. Disability progression independent of relapses activity (PIRA) has been confirmed as a frequent relapsing-remitting multiple sclerosis (RRMS) phenomenon based on Randomized Clinical Trials (RCT). Recently, RWD demonstrated that the absence of markers of inflammation (No Evidence of Disease Activity (NEDA) at 2 years did not predict long-term stability. Silent progression has been proposed to describe the insidious disability that accrues many patients who satisfy traditional criteria for relapsing-remitting MS. In this study, the investigators would like to evaluate the occurrence of the SPMS in a population of RRMS patient with an Highly Active Treatment (HAT).

Official Title
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Silent Progression Monitoring in Extreme Phenotypes. SP-MS, Despite an Effective Early Highly Active Treatment as a Paradigm SPAM Study (Silent Progression Activity Monitoring)

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Other: NO INTERVENTION


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: - Patients with RRMS (2017 Mc Donald criteria) treated with highly active treatment in the first 5 years of symptoms onset, at least 1 year, with an EDSS below 4 HAT start after April 12th 2007 (availability of Natalizumab) Naive or failure (or intolerability) to 1 or more first line DMT (injectables, teriflunomide, DMF). EDSS < or equal 4 when starting HAT EXCLUSION CRITERIA: Progressive relapsing MS at baseline Clinical or basic MRI data unavailable after on-site visit. MS diagnostic > 5 years at baseline Immunosuppressive drugs (Azathioprine, Cyclophosphamide, Mycophenolate, Methotrexate) prescribed before HAT initiation
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>Patients with RRMS (2017 Mc Donald criteria) treated with highly active treatment in the first 5 years of symptoms onset, at least 1 year, with an EDSS below 4 | Other: NO INTERVENTION<br>* NO INTERVENTION<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of baseline clinical markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | Age in years | Baseline: beginning of highly active treatment | 
| Determination of baseline clinical markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | Disease duration (which should be <5 years) in months | Baseline: beginning of highly active treatment | 
| Determination of baseline clinical markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | Expanded Disability Status Scale (EDSS) (which must be <4) | Baseline: beginning of highly active treatment | 
| Determination of baseline MRI markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | new T2 lesion(s) on brain MRI and spinal cord MRI (if available) | Baseline: beginning of highly active treatment | 
| Determination of baseline MRI markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | gadolinium enhancement on brain MRI and spinal cord MRI (if available) | Baseline: beginning of highly active treatment | 
| Determination of baseline clinical markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | Interval time between the first and the second relapse in months | Baseline: beginning of highly active treatment | 
| Determination of baseline clinical markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | Reason for HAT: naive, or switch | Baseline: beginning of highly active treatment | 
| Determination of baseline clinical markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | Number of relapses since MS onset | Baseline: beginning of highly active treatment | 
| Determination of baseline clinical markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | DMT administered since MS onset: number of DMT and type | Baseline: beginning of highly active treatment | 
| Determination of baseline MRI markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | More than 9 T2 lesions on MRI | Baseline: beginning of highly active treatment | 
| Determination of baseline MRI markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | At least 1 periventicular T2 lesion on MRI | Baseline: beginning of highly active treatment | 
| Determination of baseline MRI markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | At least 3 periventicular T2 lesions on MRI | Baseline: beginning of highly active treatment | 
| Determination of baseline MRI markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | At least 1 infratentorial T2 lesion on MRI | Baseline: beginning of highly active treatment | 
| Determination of baseline MRI markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | At least 1 spinal cord T2 lesion on MRI | Baseline: beginning of highly active treatment | 
| Determination of baseline MRI markers associated with SPMS diagnosis despite an early, practical, Highly Active Treatment. | At least 1 gadolinium enhancement T1 lesion on MRI | Baseline: beginning of highly active treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine re-baseline clinical markers associated with SPMS diagnosis despite an early, practical, HAT. | Age in years | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline clinical markers associated with SPMS diagnosis despite an early, practical, HAT. | Disease duration (which should be <5 years) in months | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline clinical markers associated with SPMS diagnosis despite an early, practical, HAT. | EDSS (which must be <4) +/- 3 months | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | new T2 lesion(s) on brain MRI and spinal cord MRI (if available) | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | gadolinium enhancement on brain MRI and spinal cord MRI (if available) | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | Interval time between the first and the second relapse in months | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | Number of relapses since MS onset | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | Number of relapse before baseline | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | Disease Modifying Therapies (DMT) administered since MS onset | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | More than 9 T2 lesions on MRI | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | At least 1 periventicular T2 lesion on MRI | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | At least 3 periventicular T2 lesion on MRI | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | At least 1 infratentorial T2 lesion on MRI | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | At least 1 spinal cord T2 lesion on MRI | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| To determine re-baseline clinical and MRI markers associated with SPMS diagnosis despite an early, practical, HAT. | At least 1 gadolinium enhancement T1 lesion on MRI | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| Detremination of the impact of different definition of SPMS according to the clinician | The definition of SPMS according to the clinician : neurological episode = start of progression as assessed by the time to develop SPMS in years. | Re-baseline definition: any patient with at least an EDSS and MRI examination performed 12 months after HAT onset. +/- 6 months (from 6 to 18 months). | 
| Dertermination of the impact of different definition of SPMS according to Lublin. | The definition of SPMS according to Lublin : progressive accumulation of disability after a primary relapsing course which must be confirmed at least 6 months after, as assessed by the time to develop SPMS in years. | at 5 years | 
| Dertermination of the impact of different definition of SPMS according to Lorscheider. | The definition of SPMS according to Lorscheider: with a minimum EDSS of 4 , an increase by 1 point if the EDSS was between 4 and 5.5, or an increase by 0.5 points if the EDSS was above 5.5, confirmed after 3 months., as assessed by the time to develop SPMS in years. | at 5 years | 
| Analyze of the influence of NEDA (No Evidence of Disease activity) | The disease activity will be evalued by the NEDA score | at baseline and at 5 years | 
| Analyze of the influence of MEDA (Mild Evidence of Disease Activity) | The disease activity will be evalued by the MEDA score | at baseline and at 5 years | 
| To find a composite score usable at baseline when prescribing early HAT in clinical practice to predict early SPMS | All baseline variables will be evaluated in association with the prescriptio of an early HAT to predict early SPMS. | at 5 years |