Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS

Study Overview
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Brief Summary
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The DELIVER-MS study seeks to answer the question: Does early treatment with highly effective DMT improve the prognosis for people with MS? This is an area of significant controversy and no data currently exist to guide treatment choices for patients and clinicians. The study results will help guide overall treatment philosophy and will be applicable not only to a wide range of existing therapies but also to new therapies, meeting a significant unmet need in patient decision making and aiding the decision for medication approval by third parties.

Official Title
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Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for the Treatment of Relapsing-Remitting Multiple Sclerosis

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Drug: Early Highly Effective Therapies Group
* Drug: Escalation Therapies Group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18 to 60 years. Established diagnosis of MS, as defined by the 2017 revision of McDonald Diagnostic Criteria (99). RRMS disease course as defined by the 2013 revisions of the MS clinical course definition (4). Participants must have evidence of active disease based on: one or more MS relapses within the last 18 months prior to screening visit or radiological evidence of MS activity (≥2 new T2 lesions within the last 12 months from screening [compared to a previous recent MRI within 18 months of screening] or ≥1 GdE demonstrated on brain or spinal cord MRI performed within the last 12 months of screening). Participants must be ambulatory with disease onset ≤ 5 years and treatment-naïve (i.e., no MS DMT at any time in the past). Participants must be eligible to receive at least one form of DMT within each treatment arm. EDSS at Baseline visit ≤ 6.5 Exclusion Criteria: Participants with contraindications to all forms of DMT in either of the treatment arms. Participants must never have received any of the following medications: natalizumab, alemtuzumab, ocrelizumab, rituximab, ofatumumab, cladribine, siponimod, interferon beta-1a, interferon beta-1b, pegylated interferon beta-1a, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, daclizumab, mitoxantrone, diroximel fumarate, ozanimod, monomethyl fumarate, ponesimod. Participants must have not received any of the following medications, for reasons other than MS, in the last 12 months: cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, leflunomide, laquinimod, atacicept, other monoclonal antibodies. Participants with clinically relevant medical or surgical conditions that, in the opinion of the investigator, would put the subject at risk by participating in the study Participants unable to provide informed consent. Contraindication or inability to undergo MRI with Gd due to metal or metal implants, allergy to Gd contrast, claustrophobia, pain, spasticity, or excessive movement related to tremor. Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition (physical, mental, or social) that, in the opinion of the PI, is likely to affect the participant's ability to comply with the study protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EHT: Early Highly-effective<br>Participants randomized to the EHT: Early Highly-effective arm will receive one of the highly effective MS therapies (Ocrevus, Lemtrada, Tysabri, Rituximab, Kesimpta) as their initial disease modifying treatment. Interventions: one of the highly effective MS therapies The randomization affects only the INITIAL treatment received. Once that treatment has been initiated, any subsequent changes are made according to standard clinical practice, regardless of randomization group. | Drug: Early Highly Effective Therapies Group<br>* Highly Effective MS Therapy group of medications<br>* Other names: Briumvi (ublituximab);|
| Experimental: ESC: Escalation<br>Participants randomized to the ESC: Escalation arm will receive any other approved MS therapy (not one of the EHT group) as their initial disease modifying treatment. Interventions: one of the MS therapies NOT in the highly effective group The randomization affects only the INITIAL treatment received. Once that treatment has been initiated, any subsequent changes are made according to standard clinical practice, regardless of randomization group. | Drug: Escalation Therapies Group<br>* Escalation MS Therapy group of medications<br>* Other names: Ponvory (ponesimod);|
| No Intervention: OBS: Observational<br>Participants will not be restricted to a group of MS therapies. Participants enter this arm if they are not comfortable with randomization, are not eligible to receive any of the options in a randomized arm, or are not able to secure insurance coverage for any therapy in a randomized arm. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain volume loss, baseline to month 36 | 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. | Baseline to 36 months | 
| EDSS+, month 48 to month 72 | 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. | 48 months to 72 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain volume loss, month 6 to month 36 | 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. | Month 6 to month 36 | 
| Proportion of participants with progression | 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. | Baseline to 36 months | 
| Change in MSIS-29, baseline to 36 months | Change in MSIS-29 responses from participants | Baseline to 36 months | 
| Change in Neuro-QOL, baseline to 36 months | 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 | Baseline to 36 months | 
| Time to reach SPMS, month 48 to month 72 | 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 72 months Proportion of participants with a 20% or greater change in T25FW at 72 months. Proportion of participants with a 20% or greater change in 9HPT at 72 months. Proportion of participants with a 20% or greater change in the SDMT at 72 months. | 48 months to 72 months | 
| Efficacy difference between EHT and ESC, month 48 to month 72 | 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. | 48 months to 72 months | 
| Safety difference between EHT and ESC, month 48 to month 72 | 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 | 48 months to 72 months |