Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS)

August 14, 2023 updated by: Daniel Ontaneda, MD, The Cleveland Clinic

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

800

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Sarah Planchon Pope, PhD
  • Phone Number: 216-636-1232
  • Email: planchs@ccf.org

Study Locations

  • United Kingdom
      • Nottingham, United Kingdom, NG7 2UH
        • Recruiting
        • Nottingham University Hospitals NHS Trust, Queens Medical Centre
        • Contact:
        • Principal Investigator:
          • Nikos Evangelou, MD, DPhil
    • England
      • Coventry, England, United Kingdom, CV2 2DX
        • Recruiting
        • University Hospitals Coventry and Warwickshire
        • Contact:
        • Principal Investigator:
          • Tarunya Arun
      • Frimley, England, United Kingdom, GU16 7UJ
        • Not yet recruiting
        • Frimley Park
        • Principal Investigator:
          • Matthew Craner
      • Leeds, England, United Kingdom, LS1 3EX
        • Recruiting
        • The Leeds Teaching Hospitals NHS Trust, Leeds General Infirmary
        • Contact:
        • Principal Investigator:
          • Oliver Lily, MD
      • Leicester, England, United Kingdom, LE1 5WW
      • London, England, United Kingdom, W6 8RF
        • Recruiting
        • Imperial College Healthcare NHS Trust, Charing Cross Hospital
        • Contact:
        • Principal Investigator:
          • Richard Nicholas, MD
      • London, England, United Kingdom, WC1N 3BG
        • Recruiting
        • University College London Hospitals NHS Foundation Trust, University College Hospital
        • Contact:
        • Principal Investigator:
          • Wallace Brownlee, MD
      • Manchester, England, United Kingdom, M6 8HD
        • Recruiting
        • Salford Royal NHS Foundation Trust, Salford Hospital
        • Contact:
        • Principal Investigator:
          • David Rog, MD
      • Oxford, England, United Kingdom, OX3 9DU
        • Recruiting
        • Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital
        • Contact:
        • Principal Investigator:
          • Matthew Craner, MD
      • Plymouth, England, United Kingdom, PL6 8DH
        • Recruiting
        • University Hospitals Plymouth NHS Trust, Derriford Hospital
        • Contact:
        • Principal Investigator:
          • Jeremy Hobart, MD
      • Sheffield, England, United Kingdom, S5 7AT
        • Recruiting
        • Sheffield Teaching Hospitals
        • Contact:
        • Principal Investigator:
          • David Paling
      • Stoke, England, United Kingdom, ST4 6QG
        • Recruiting
        • University Hospitals of North Midlands
        • Contact:
        • Principal Investigator:
          • Seema Karla
    • Scotland
      • Edinburgh, Scotland, United Kingdom, EH16 4SA
        • Recruiting
        • Royal Infirmary of Edinburgh
        • Contact:
        • Principal Investigator:
          • Don Mahad
    • Wales
      • Cardiff, Wales, United Kingdom, CF14 4XW
        • Recruiting
        • Cardiff and Vale University Local Health Board, University Hospital of Wales
        • Contact:
        • Principal Investigator:
          • Emma Tallantyre, MD
      • Newport, Wales, United Kingdom, NP19 0BH
        • Recruiting
        • Aneurin Bevan Local Health Board Headquarters, Royal Gwent Hospital
        • Contact:
        • Principal Investigator:
          • Fady Joseph, ND
      • Swansea, Wales, United Kingdom, SA6 6NL
        • Recruiting
        • Swansea Bay University Local Health Board, Morriston Hospital
        • Contact:
        • Principal Investigator:
          • Owen Pearson, MD
  • United States
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • University of Colorado-Anschutz Medical Campus
        • Contact:
        • Principal Investigator:
          • Enrique. Alvarez,, MD,PhD
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • Recruiting
        • University of Minnesota
        • Contact:
        • Principal Investigator:
          • William Schmalsteig, MD
      • Rochester, Minnesota, United States, 55902
        • Recruiting
        • Mayo Clinic
        • Contact:
        • Principal Investigator:
          • Orhun Kantarci
    • Nevada
      • Las Vegas, Nevada, United States, 89106
        • Recruiting
        • Cleveland Clinic Lou Ruvo Center for Brain Health
        • Principal Investigator:
          • Carrie Hersh, DO, MSc
        • Contact:
    • New York
      • Buffalo, New York, United States, 14202
        • Recruiting
        • University of Buffalo
        • Contact:
        • Principal Investigator:
          • Bianca Weinstock-Guttman, MD
      • Rochester, New York, United States, 14642
        • Recruiting
        • University Rochester Medical Center
        • Contact:
        • Principal Investigator:
          • Megan Hyland, MD
    • Ohio
      • Cincinnati, Ohio, United States, 45267
        • Recruiting
        • University of Cincinnati
        • Principal Investigator:
          • Aram Zabeti, MD
        • Contact:
      • Cleveland, Ohio, United States, 44195
        • Recruiting
        • Cleveland Clinic
        • Principal Investigator:
          • Daniel Ontaneda, MD, PhD
        • Contact:
      • Columbus, Ohio, United States, 43214
        • Recruiting
        • Ohio Health
        • Contact:
        • Principal Investigator:
          • Jacqueline A Nicholas, MD, MPH
    • Texas
      • Austin, Texas, United States, 78712
      • Houston, Texas, United States, 77030
        • Recruiting
        • Baylor College of Medicine, Houston
        • Contact:
        • Principal Investigator:
          • George Hutton, MD
      • Houston, Texas, United States, 77030
        • Recruiting
        • UTHealth-Houston
        • Contact:
        • Principal Investigator:
          • Rajesh Gupta, MD
    • Virginia
      • Charlottesville, Virginia, United States, 22903
        • Recruiting
        • University of Virginia
        • Contact:
        • Principal Investigator:
          • Mini Singh, MD
      • Richmond, Virginia, United States, 23284
        • Recruiting
        • Virginia Commonwealth University
        • Principal Investigator:
          • Myla Goldman, MD
        • Contact:
    • Wisconsin
      • Madison, Wisconsin, United States, 53705
        • Recruiting
        • University of Wisconsin-Madison
        • Contact:
        • Principal Investigator:
          • Natasha Frost, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: EHT: Early Highly-effective

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
Highly Effective MS Therapy group of medications
Other Names:
  • Lemtrada (alemtuzumab)
  • Ocrevus (ocrelizumab)
  • Tysabri (natalizumab)
  • Rituxan (rituximab)
  • Kesimpta (ofatumumab)
  • Briumvi (ublituximab)
Experimental: ESC: Escalation

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
Escalation MS Therapy group of medications
Other Names:
  • 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)
No Intervention: OBS: Observational

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?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Brain volume loss, month 6 to month 36
Time Frame: 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
Time Frame: 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.
Baseline to 36 months
Change in MSIS-29, baseline to 36 months
Time Frame: Baseline to 36 months
Change in MSIS-29 responses from participants
Baseline to 36 months
Change in Neuro-QOL, baseline to 36 months
Time Frame: 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
Time Frame: 48 months to 72 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 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
Time Frame: 48 months to 72 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.
48 months to 72 months
Safety difference between EHT and ESC, month 48 to month 72
Time Frame: 48 months to 72 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
48 months to 72 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Cleveland Clinic

Collaborators

University of Nottingham

Investigators

  • Principal Investigator: Daniel Ontaneda, MD, MSc, The Cleveland Clinic
  • Principal Investigator: Nikos Evangelou, MD, DPhil, University of Nottingham

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 3, 2019

Primary Completion (Estimated)

April 30, 2030

Study Completion (Estimated)

September 1, 2030

Study Registration Dates

First Submitted

May 14, 2018

First Submitted That Met QC Criteria

May 14, 2018

First Posted (Actual)

May 24, 2018

Study Record Updates

Last Update Posted (Actual)

August 16, 2023

Last Update Submitted That Met QC Criteria

August 14, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CCF 18-326

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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