Early Intensive or Escalation Therapy for Relapsing-Remitting Multiple Sclerosis?

Every diagnosis of relapsing-remitting multiple sclerosis (RRMS) presents patients and clinicians with a fundamental choice of treatment strategy: Should they opt for an “early highly effective treatment” (EHT) approach, using more potent therapies from the outset, or an escalation approach, beginning with safer but potentially less effective treatments and escalating as needed?

This crucial question has been the focus of the multicenter DELIVER-MS study, a three-year randomized clinical trial of 400 patients with RRMS assigned to either the EHT approach or the escalation approach to assess the effect on brain volume loss on MRI. Now, as enrollees in DELIVER-MS complete their three-year follow-up, the study is shifting to looking at clinical disability in a long-term extension study to assess disability outcomes over a total follow-up of nine years.

“There are currently no definitive data from randomized controlled trials to guide the choice between early intensive and escalation approaches,” notes the study’s U.S. principal investigator, Daniel Ontaneda, MD, PhD, a neurologist with Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research. “Both DELIVER-MS and this extension study (“Comparing the long-term effectiveness of initial treatment approaches for relapsing-remitting multiple sclerosis on the prevention of disability”) are intended to address a significant area of uncertainty and help neurologists and patients make better-informed treatment decisions.”

Like the initial DELIVER-MS study, the long-term extension study is funded by the Patient-Centered Outcomes Research Institute (PCORI); the extension also has co-funding from the National Multiple Sclerosis Society and the UK Multiple Sclerosis Society. Dr. Ontaneda is leading the study with Dr. Emma Tallantyre of Cardiff University in the United Kingdom, who serves as U.K. principal investigator.

An assessment of treatment philosophies

The study’s 400 participants come from 29 sites in the U.S. and U.K, including Cleveland Clinic. Patients randomized to the EHT arm receive first-line therapy with one of six monoclonal antibodies recognized for high efficacy and a generally less desirable safety profile relative to other disease-modifying therapies (DMTs) for RRMS: alemtuzumab, natalizumab, rituximab, ocrelizumab, ofatumumab or ublituximab. Patients randomized to the escalation arm are started on any other DMTs approved for RRMS, with subsequent escalation to more-potent therapies if disease activity continues.

“The aim is to compare these overarching treatment philosophies rather than individual medications,” explains Dr. Ontaneda.

Key outcome measures

The primary objective of the long-term extension study is to determine whether the EHT approach is more effective than the escalation approach in reducing the time to reach a multidimensional composite of confirmed disability worsening. This composite endpoint requires worsening on at least one of three components — the Expanded Disability Status Scale, the 9-hole peg test and the timed 25-foot walk — confirmed at a subsequent visit after 12 months.

A number of secondary endpoints will assess more specific measures within each of these three components. Patient-reported outcomes also will be evaluated, including changes in patient-perceived MS symptoms and changes in quality of life. And safety will be assessed in terms of the proportion and rate of serious adverse events and the proportion of participants who discontinue DMT due to safety or tolerability issues.

“We believe that brain volume loss on MRI — the primary endpoint in DELIVER-MS — is a surrogate outcome for long-term disability,” says Dr. Ontaneda. “Unfortunately, we couldn’t definitively assess long-term disability in that initial three-year study without enrolling a prohibitively large number of patients, as previous studies show that differences in disability accumulation begin to clearly manifest only after about three years of treatment. By following our original cohort of patients over a much longer time, we will now be able to detect any statistically significant difference in the outcome that matters most to patients — long-term disability progression. Patients really want to know how much mobility and independence they’re likely to have in 10 years.”

The study will continue to assess the effects of the treatment strategies on brain volume loss and other MRI measures to determine their long-term impact in this realm as well.

An effort to replicate real-world practice

DELIVER-MS was designed as a pragmatic randomized trial, and that design carries over to its long-term extension. A key example is the study’s intentionally broad inclusion criteria, which encompass most individuals initiating DMT for RRMS across both academic and community-based sites.

Additionally, the study has a parallel 400-patient observational cohort that will continue through the long-term extension. “When we were recruiting, if patients did not want to take part in the randomized trial, we offered to put them in an observational cohort where they could decide on their treatment approach with their physician and we would still evaluate them in the same way as in the randomized trial,” Dr. Ontaneda explains. “This is another reflection of clinical practice, in that it reveals what patients and their physicians are actually choosing.” He notes that only about 60% of patients in the observational cohort opted for EHT, and that the share was considerably lower — 37% — among the U.K. participants.

Crucial insights expected regardless of result specifics

Irrespective of the direction of the ultimate findings, Dr. Ontaneda believes this study will be very important to the management of RRMS.

“If we find that EHT medications really do improve outcomes without an increase in risks over the course of nine years, we can confidently say we should favor more highly effective therapies from the start,” he says. “In contrast, if we find that patients don’t necessarily need these EHT medications to achieve comparably good long-term disability outcomes, then so much better for patients, as they can initially opt for less-risky medications without compromising efficacy.”