Treatment of Inflammatory Myelitis and Optic Neuritis With Early vs Rescue Plasma Exchange (TIMELY-PLEX)

Study Population and Setting

The proposal will recruit participants presenting to participating sites with severe ON or severe TM to two separate sub-trials. The detailed inclusion and exclusion criteria for each sub-trial are listed below:

Optic Neuritis Sub-Trial:

Inclusion criteria:

• ≥18 years of age

• MRI orbits demonstrating evidence of new T2 hyperintensity and/or post-gadoliniumcontrast enhancement of the optic nerve(s) and meeting the clinical criteria forOptic Neuritis

• Visual acuity 20/200 or worse

• Within 8 days of onset of visual symptoms

• Able to initiate PLEX within 72h of the first dose of HDCS (if randomized to the "Early PLEX" treatment arm)

• Able to sign and date informed consent form

• Willingness to comply with all study procedures and availability for the duration ofthe study

Exclusion criteria:

• Evidence of prior episode of optic neuritis in the affected eye (by history orophthalmological evaluation)

• Ophthalmological comorbidity that would significantly affect best corrected visualacuity or visual fields

• Pregnancy

• Presence of any contraindication to receiving HDCS or PLEX, including, but notlimited to, hemodynamic instability, significant bleeding/coagulopathy, or sepsis.

• Any medical condition that, in the opinion of the investigator, may interfere withthe patient's participation in the trial, pose any added risk for the patient, orconfound the assessment of the patient (including but not limited to concurrentneurological disease and/or medical comorbidity)

• Treatment with any investigational agent within 6 months of baseline or fivehalf-lives of the investigational agent (whichever is longer)

• Ongoing/prior treatment with immune-modulating/immunosuppressive therapy including:

• Mycophenolate mofetil, azathioprine, methotrexate, fingolimod, siponimod,ponesimod, ozanimod, tocilizumab, satralizumab, eculizumab or ravulizumabwithin 3 months of randomization

• Anti-CD20 (rituximab, ocrelizumab, ofatumumab, ublituximab) or anti-CD19 (inebilizumab) therapy within 6 months of randomization

• Intravenous or subcutaneous immune globulin within 3 months of randomization

• Plasma exchange within 3 months of randomization

• Interferon-beta, glatiramer acetate, fumarates (dimethyl fumarate, monomethylfumarate, diroximel fumarate) within 1 month of randomization

• Teriflunomide use within prior 24 months

• Systemic corticosteroid therapy (intravenous or oral; excluding inhaled ortopical corticosteroids) within 1 month of randomization

• Any previous treatment with alemtuzumab, cladribine, mitoxantrone orcyclophosphamide

• Previous treatment with any immune-modulating or immunosuppressive therapy notmentioned above within 6 months of randomization or five-half-lives (whichever islonger)

Transverse Myelitis Sub-Trial:

Inclusion criteria:

• ≥18 years of age

• Diagnosis of Transverse Myelitis (defined based on modified criteria adapted fromthe 2002 Transverse Myelitis Consortium Working Group; ALL are required)

• Development of sensory, motor and/or autonomic symptomatology attributable tospinal cord dysfunction

• Onset of symptoms to nadir >12 hours

• Exclusion of extra-axial compressive etiology by neuroimaging

• Demonstration of inflammation within the spinal cord by presence ofintramedullary T2 lesion (post-gadolinium enhancing OR non-enhancing) on MRI

• Expanded Disability Status Scale [EDSS] ≥3.0 (excluding visual and cerebralfunctional systems)

• EDSS Pyramidal Functional System Score ≥ 2

• Within 8 days of onset of motor symptoms

• Able to initiate PLEX within 48h of the first dose of HDCS (if randomized to the "Early PLEX" treatment arm)

• Able to sign and date informed consent form

• Willingness to comply with all study procedures and availability for the duration ofthe study

Exclusion criteria:

• Pre-existing ambulatory, motor, sensory, or bowel/bladder disability of any causethat could confound trial assessments

• Fulfillment of possible, probable or definite spinal cord infarction diagnosis perproposed diagnostic criteria (Zalewski et al. JAMA Neurology 2018)

• History of radiation to the spine

• Pregnancy

• High clinical suspicion for infectious etiology of myelitis (e.g., fever, rash orother findings)

• Presence of any contraindication to receiving HDCS or PLEX, including, but notlimited to, hemodynamic instability, significant bleeding/coagulopathy, or sepsis.

• Any medical condition that, in the opinion of the investigator, may interfere withthe patient's participation in the trial, pose any added risk for the patient, orconfound the assessment of the patient (including but not limited to concurrentneurological disease and/or medical comorbidity)

• Treatment with any investigational agent within 24 weeks of baseline or fivehalf-lives of the investigational agent (whichever is longer)

• Ongoing/prior treatment with immune-modulating/immunosuppressive therapyincluding: Mycophenolate mofetil, azathioprine, methotrexate, fingolimod,siponimod, ponesimod, ozanimod, tocilizumab, satralizumab, eculizumab orravulizumab within 3 months of randomization

• Anti-CD20 (rituximab, ocrelizumab, ofatumumab, ublituximab) or anti-CD19 (inebilizumab) therapy within 6 months of randomization

• Intravenous or subcutaneous immune globulin within 3 months of randomization

• Plasma exchange within 3 months of randomization

• Interferon-beta, glatiramer acetate, fumarates (dimethyl fumarate, monomethylfumarate, diroximel fumarate) within 1 month of randomization

• Teriflunomide use within prior 24 months

• Systemic corticosteroid therapy (intravenous or oral; excluding inhaled ortopical corticosteroids) within 1 month of randomization

• Any previous treatment with alemtuzumab, cladribine, mitoxantrone orcyclophosphamide

• Previous treatment with any immune-modulating or immunosuppressive therapy notmentioned above within 6 months of randomization or five-half-lives (whichever islonger)