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How the SPRINT-MS Follow-On Study Aims to Enhance Future Trials of Progressive Multiple Sclerosis

In search of optimal imaging biomarkers, best methods for long-term follow-up

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When the SPRINT-MS trial concluded six years ago, it delivered promising findings about the potential of the medication ibudilast to slow progression of whole brain atrophy in people with progressive multiple sclerosis (MS). Now investigators with the phase 2 multicenter study are launching the SPRINT-MS Follow-On Study with ambitions that extend beyond that single medication — namely, to potentially improve clinical testing in progressive MS more broadly.


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“The goal of this follow-on study is twofold,” says Robert Fox, MD, principal investigator of both SPRINT-MS and the new study. “First, we aim to leverage the two-year imaging and clinical data collected during the SPRINT-MS trial to evaluate the ability of the study’s imaging biomarkers to predict long-term clinical outcomes. Second, we hope to learn how to find patients long after a study has completed. Through this effort, we hope to understand better ways to conduct both clinical trials and long-term follow-up studies in progressive MS,”

No one in the MS field has comprehensively described how to effectively find and follow patients over the long term, notes Dr. Fox, a staff neurologist with Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research. “Additionally, no one really knows which MRI measures are most predictive of the long-term course of progressive MS,” he explains. “We’re aiming to fill both those gaps to enhance the quality of future MS studies.”

SPRINT-MS as a springboard for further insights

SPRINT-MS (N Engl J Med. 2018;379:846-855) randomized 255 patients with primary or secondary progressive MS to oral ibudilast or placebo for two years. Ibudilast was found to slow the rate of brain atrophy on MRI — the study’s primary endpoint — by nearly half relative to placebo over the two-year study.

“This finding was encouraging, but the long-term clinical relevance of this slowing of atrophy remains uncertain,” Dr. Fox observes. “There is a need in phase 2 trials of progressive MS to have clinically relevant biomarkers that reflect the underlying disease process and predict clinical benefit, which ultimately is slowing of disability.”

Although whole brain atrophy is currently the most widely used outcome measure for studies of patients with progressive MS, its utility is limited by its lack of precision as a single summative measure across the entire brain and by considerable variability. “We suspect there will be other, more granular MRI measures that will provide a more precise and dynamic characterization and be more predictive of further disability than whole brain atrophy,” Dr. Fox says.

To that end, he and his co-investigators are turning to more than a dozen advanced MRI measures that were analyzed from the SPRINT-MS dataset in addition to brain atrophy, such as magnetization transfer ratio, diffusion tensor imaging, cortical thickness and others.

“We already had these measures captured, so we decided to follow up with the patients to see how they were doing now, and then use that information to understand which of the MRI measures — or combination of measures — was most predictive of long-term disease progression,” Dr. Fox explains.

What the follow-up entails

To achieve this, investigators from the 28 SPRINT-MS trial sites in the U.S. will attempt to follow up with all 255 study participants and invite them for a single clinical visit approximately 8.5 to 11 years after their enrollment in the trial. The visit will assess disability in terms of the following:

  • Interval MS history, including the use of disease-modifying therapies and relapses
  • Expanded Disability Status Scale examination
  • Portions of the MS Functional Composite (Timed 25-Foot Walk, 9-Hole Peg Test, Symbol Digit Modalities Test, low-contrast visual acuity test)
  • Patient-reported outcomes


If study participants are unable to travel to a study center, personnel from a study site will travel to the patient or, if necessary, the visit can be conducted virtually.

Disability progression will then be statistically analyzed in the context of the two-year change in each of the MRI measures from the initial SPRINT-MS imaging dataset, with factors such as treatment assignment during the trial and subsequent MS therapies taken into account.

A multipronged objective

The study has several goals:

  • To evaluate the clinical relevance of short-term changes in advanced MRI measures (i.e., during the initial two-year study) for long-term evolution of progressive MS.
  • To identify the strongest imaging biomarkers — or combination of biomarkers — for predicting clinical progression and thus for use in phase 2 studies of therapies for progressive MS. “Clinical correlations will be considered along with pragmatic aspects of image acquisition and analysis, as well as longitudinal variability,” Dr. Fox notes. “We will be looking not just at clinical relevance but also at reproducibility, biologic variability and dynamic change of biomarkers over time. The ultimate goal is to find biomarkers that can enable future trials to be conducted more efficiently — in fewer patients and more rapidly.”
  • To better understand and overcome obstacles to conducting long-term follow-up studies of patients with progressive MS. “Not much is known about how to find people who previously participated in MS studies,” Dr. Fox says. He and his co-investigators will use a range of approaches, from follow-up with patients’ contacts from the medical record to searching online resources such as publicly reported voting records (publicly accessible in Ohio and some other states) to inquiries with nursing homes, among others. They will report their observations in an effort to facilitate better long-term follow-up in future MS studies.


“Progressive MS has some commonalities with other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases, so what we learn from this study may have relevance to improving trials and follow-up in other disorders as well,” Dr. Fox notes.

The study, which is supported by a $1.25 million grant from the National MS Society, is starting this summer, with results expected by the spring of 2025.


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