Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS

NCT03535298 | Active Not Recruiting Phase 4 FDA Drug

• 1 other identifier: CCF 18-326/23-453
• Study Type: interventional
• Target: 800
• Locations: 2 countries
• Sites: 30

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.

Conditions

Multiple Sclerosis, Relapsing-Remitting

Outcome Measures

Primary Outcomes (2)

• 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 108

  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 108 months

Secondary Outcomes (7)

• Brain volume loss, month 6 to month 36

  Month 6 to month 36

• Proportion of participants with progression

  Baseline to 36 months

• Change in MSIS-29, baseline to 36 months

  Baseline to 36 months

• Change in Neuro-QOL, baseline to 36 months

  Baseline to 36 months

• Time to reach SPMS, month 48 to month 108

  48 months to 108 months

Study Arms (3)

EHT: Early Highly-effective

EXPERIMENTAL

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

ESC: Escalation

EXPERIMENTAL

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

OBS: Observational

NO INTERVENTION

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.

Interventions

Early Highly Effective Therapies Group DRUG

Highly Effective MS Therapy group of medications

Also known as: Lemtrada (alemtuzumab), Ocrevus (ocrelizumab), Tysabri (natalizumab), Rituxan (rituximab), Kesimpta (ofatumumab), Briumvi (ublituximab)

EHT: Early Highly-effective

Escalation Therapies Group DRUG

Escalation MS Therapy group of medications

Also known as: Betaseron (beta interferon), Copaxone (glatiramer acetate), Aubagio (teriflunomide), Extavia (beta interferon), Gilenya (fingolimod), Glatopa (glatiramer acetate), Plegridy (beta interferon), Rebif (beta interferon), Tecfidera (dimethyl fumarate), Avonex (beta interferon), Mavenclad (cladribine), Mayzent (siponimod), Vumerity (diroximel fumarate), Zeposia (ozanimod), Bafiertam (monomethyl fumarate), Ponvory (ponesimod)

ESC: Escalation

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Cleveland Clinic: lead
• University of Nottingham: collaborator

Study Sites (30)

University of Colorado-Anschutz Medical Campus

Aurora, Colorado, 80045, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Mayo Clinic

Rochester, Minnesota, 55902, United States

Location

Cleveland Clinic Lou Ruvo Center for Brain Health

Las Vegas, Nevada, 89106, United States

Location

University of Buffalo

Buffalo, New York, 14202, United States

Location

University Rochester Medical Center

Rochester, New York, 14642, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45267, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Ohio Health

Columbus, Ohio, 43214, United States

Location

UT-Austin

Austin, Texas, 78712, United States

Location

Baylor College of Medicine, Houston

Houston, Texas, 77030, United States

Location

UTHealth-Houston

Houston, Texas, 77030, United States

Location

University of Virginia

Charlottesville, Virginia, 22903, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23284, United States

Location

University of Wisconsin-Madison

Madison, Wisconsin, 53705, United States

Location

University Hospitals Coventry and Warwickshire

Coventry, England, CV2 2DX, United Kingdom

Location

The Leeds Teaching Hospitals NHS Trust, Leeds General Infirmary

Leeds, England, LS1 3EX, United Kingdom

Location

University Hospitals Leicester

Leicester, England, LE1 5WW, United Kingdom

Location

Imperial College Healthcare NHS Trust, Charing Cross Hospital

London, England, W6 8RF, United Kingdom

Location

University College London Hospitals NHS Foundation Trust, University College Hospital

London, England, WC1N 3BG, United Kingdom

Location

Salford Royal NHS Foundation Trust, Salford Hospital

Manchester, England, M6 8HD, United Kingdom

Location

Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital

Oxford, England, OX3 9DU, United Kingdom

Location

University Hospitals Plymouth NHS Trust, Derriford Hospital

Plymouth, England, PL6 8DH, United Kingdom

Location

Sheffield Teaching Hospitals

Sheffield, England, S5 7AT, United Kingdom

Location

University Hospitals of North Midlands

Stoke, England, ST4 6QG, United Kingdom

Location

Royal Infirmary of Edinburgh

Edinburgh, Scotland, EH16 4SA, United Kingdom

Location

Cardiff and Vale University Local Health Board, University Hospital of Wales

Cardiff, Wales, CF14 4XW, United Kingdom

Location

Aneurin Bevan Local Health Board Headquarters, Royal Gwent Hospital

Newport, Wales, NP19 0BH, United Kingdom

Location

Swansea Bay University Local Health Board, Morriston Hospital

Swansea, Wales, SA6 6NL, United Kingdom

Location

Nottingham University Hospitals NHS Trust, Queens Medical Centre

Nottingham, NG7 2UH, United Kingdom

Location

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting

Interventions

Alemtuzumab; ocrelizumab; Natalizumab; Rituximab; ofatumumab; ublituximab; Interferon beta-1b; Interferon-beta; Glatiramer Acetate; teriflunomide; Fingolimod Hydrochloride; Coat Protein Complex I; peginterferon beta-1a; Interferon beta-1a; Dimethyl Fumarate; Cladribine; siponimod; diroximel fumarate; ozanimod; monomethyl fumarate; ponesimod

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Antibodies, Monoclonal, Murine-Derived; Interferon Type I; Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors; Sphingosine; Amino Alcohols; Alcohols; Organic Chemicals; Propylene Glycols; Glycols; Amines; Vesicular Transport Proteins; Membrane Proteins; Fumarates; Dicarboxylic Acids; Acids, Acyclic; Carboxylic Acids; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Daniel Ontaneda, MD, MSc

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

• Nikos Evangelou, MD, DPhil

  University of Nottingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 14, 2018
• First Posted: May 24, 2018
• Study Start: January 3, 2019
• Primary Completion (Estimated): July 30, 2027
• Study Completion (Estimated): July 30, 2027
• Last Updated: August 28, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (15); GB (15)