Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS

To determine whether an EHT approach to DMT, defined as use of one of four monoclonal antibodies (alemtuzumab, natalizumab, rituximab, or ocrelizumab) as first-line therapy, is more effective than an escalation of treatment approach in reducing normalized whole brain volume loss measured using MRI in PwRRMS from Baseline to Month 36.

To determine whether an EHT approach to DMT, defined as use of one of six monoclonal antibodies (alemtuzumab, natalizumab, rituximab, ocrelizumab, ofatumumab, ublituximab) as first-line therapy, is more effective than an escalation of treatment approach in reducing time to reach a multidimensional composite comprised of EDSS+ worsening. EDSS+ worsening will be defined as worsening on ⩾ 1 of the 3 components: EDSS, 9HPT, or T25FW, which is confirmed at another visit after 12 months. EDSS worsening will be defined as a ⩾1.0-point increase from a baseline score of ⩽5.5 or a ⩾0.5-point increase from a baseline score of ⩾6.0. T25FW and 9HPT worsening will be defined as ⩾20% worsening from baseline.

To determine whether an EHT approach to DMT, defined as use of one of four monoclonal antibodies (alemtuzumab, natalizumab, rituximab, or ocrelizumab) as first-line therapy, is more effective than an escalation of treatment approach in reducing normalized whole brain volume loss measured using MRI in PwRRMS from Month 6 to Month 36.

Proportion of participants with a multidimensional composite comprised of EDSS progression (>1.5 points for those with EDSS of 0 at Baseline, ≥1.0 for those with EDSS of 0.5-5.0 at Baseline, and >0.5 points for those with EDSS above 5.0 at Baseline), 20% change in MSFC-4 subcomponents (T25FW, 9HPT), 10% in SDMT or, 1 line change in LCLA confirmed over 12 months.

Change in MSIS-29 responses from participants

11 subscales, each is scored separately, there is no composite score

Physical Domains:

Upper Extremity Function (Fine Motor, ADL):

Higher scores indicate: Better Functioning

Lower Extremity Function (Mobility):

Higher scores indicate: Better Functioning

Fatigue:

Higher scores indicate: Worse Functioning

Sleep Disturbance:

Higher scores indicate: Worse Functioning

Mental Domains:

Cognition Function:

Higher scores indicate: Better Functioning

Stigma:

Higher scores indicate: Worse Functioning

Anxiety:

Higher scores indicate: Worse Functioning

Depression:

Higher scores indicate: Worse Functioning

Positive Affect and Well -being:

Higher scores indicate: Better Functioning

Social Domains:

Ability to Participate in Social Roles and Activities:

Higher scores indicate: Better Functioning

Satisfaction with Social Roles and Activities:

Higher scores indicate: Better Functioning

To determine the efficacy of an EHT approach as compared to an escalation approach as reflected by the following:

• Time to reach secondary progressive MS (SPMS) as defined by worsening on the EDSS (3 strata definition for EDSS worsening plus EDSS score of ≥4 and pyramidal score ≥2), confirmed at 12 months, over 108 months
• Proportion of participants with a 20% or greater change in T25FW at 108 months.
• Proportion of participants with a 20% or greater change in 9HPT at 108 months.
• Proportion of participants with a 20% or greater change in the SDMT at 108 months.

To determine the efficacy of an EHT approach as compared to an escalation approach as reflected in the following patient-reported outcomes:

• The change in participant-perceived symptoms as measured by the MSIS-29.
• The change in participant quality of life as measured by Neuro-QOL.

To determine the safety of an EHT approach as compared to an escalation approach as reflected in the following:

• Proportion of participants with SAEs
• Rate of SAEs
• Proportion of participants with DMT discontinuation due to safety or tolerability concerns
• Cumulative on-therapy TSQM Response scores