Multiple Sclerosis, Relapsing-Remitting
Conditions
Brief summary
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.
Detailed description
DELIVER-MS is a multi-center pragmatic comparative effectiveness randomized clinical trial with additional-parallel observational cohort. It aims to enroll up to 400 individuals newly diagnosed with RRMS and randomize them 1:1 to Early Highly Effective (EHT) or Escalation (ESC) treatment paradigms, based on the use of different disease modifying therapies (DMT) as first-line therapy. EHT approach to DMT is defined as use of one of five monoclonal antibodies (alemtuzumab, natalizumab, rituximab, ocrelizumab, ofatumumab, ublituximab) as first-line therapy. ESC approach is defined as initiating any other approved MS DMT as first-line therapy, then escalating to a more effective therapy upon disease activity. Once randomized, the Neurologist and Participant decide which DMT within the arm is most appropriate. After the initial DMT is initiated, if a DMT change is needed, the second-line therapy may be chosen from either arm, regardless of randomization. The randomization only applies to the initial DMT choice. Up to 400 individuals who do are not amenable to randomization or who agree to randomization but are not approved for coverage for a medication in the arm to which they were randomized will enter the Observational Arm. In the Observational Arm, the DMT chosen is from any approved DMT for MS and is chosen by the Neurologist and participant. All study procedures throughout are identical between the randomized and observation alarm, except for the randomization. The primary objective for the initial 36 months of the study is normalized whole brain volume loss, measured using MRI from baseline to Month 36. The primary objective for the long term extension of the study (Months 48-108) is the EDSS+, a composite measure of clinical disability based on the EDSS and MSFC. The study is performed primarily in tertiary MS Centers in the US and UK.
Interventions
DRUGEarly Highly Effective Therapies Group
Highly Effective MS Therapy group of medications
DRUGEscalation Therapies Group
Escalation MS Therapy group of medications
Sponsors
The Cleveland Clinic
University of Nottingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women aged 18 to 60 years. 2. Established diagnosis of MS, as defined by the 2017 revision of McDonald Diagnostic Criteria (99). 3. RRMS disease course as defined by the 2013 revisions of the MS clinical course definition (4). 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). 5. Participants must be ambulatory with disease onset ≤ 5 years and treatment-naïve (i.e., no MS DMT at any time in the past). 6. Participants must be eligible to receive at least one form of DMT within each treatment arm. 7. EDSS at Baseline visit ≤ 6.5
Exclusion criteria
1. Participants with contraindications to all forms of DMT in either of the treatment arms. 2. 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. 3. 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. 4. 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 5. Participants unable to provide informed consent. 6. 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. 7. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain volume loss, baseline to month 36 | Baseline to 36 months | 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. |
| EDSS+, month 48 to month 108 | 48 months to 108 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brain volume loss, month 6 to month 36 | 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. |
| Proportion of participants with progression | Baseline to 36 months | 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, baseline to 36 months | Baseline to 36 months | Change in MSIS-29 responses from participants |
| Change in Neuro-QOL, baseline to 36 months | 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 |
| Time to reach SPMS, month 48 to month 108 | 48 months to 108 months | 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. |
| Efficacy difference between EHT and ESC, month 48 to month 108 | 48 months to 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. |
| Safety difference between EHT and ESC, month 48 to month 108 | 48 months to 108 months | 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 |
Countries
United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORDaniel Ontaneda, MD, MSc
The Cleveland Clinic
PRINCIPAL_INVESTIGATORNikos Evangelou, MD, DPhil
University of Nottingham
Outcome results
None listed