Researchers at the Belgian National MS Center in Melsbroek, working with collaborators in the Netherlands, the United States, and Canada, examined whether hand function, assessed with the Nine Hole Peg Test, could serve as a reliable primary outcome measure in non-ambulatory people with progressive multiple sclerosis. Their findings, published in the Journal of Neurology, show that hand function deteriorates measurably and consistently in this population over two years—and that a particular way of scoring the test may be sensitive enough to power future clinical trials in a group of patients who have long been left on the sidelines of therapeutic research.

The Nine Hole Peg Test is among the simplest instruments in neurology. It asks participants to pick up nine small pegs, one at a time, place them into a series of holes, and then remove them again, with the entire sequence timed in seconds. What the test lacks in sophistication it makes up for in practicality: it is quick, inexpensive, reproducible, and executable by people who use wheelchairs. It has long been a component of the Multiple Sclerosis Functional Composite, but it has rarely been trusted to carry the weight of a primary endpoint on its own. The new research set out to test whether it could.

The team drew on a well-characterized database of patients followed at the Melsbroek center, applying strict inclusion criteria. In total, 131 people were included, all with progressive multiple sclerosis, all with a baseline EDSS score of at least 7.0—indicating severe disability and, in most cases, inability to walk more than a few meters even with assistance—and all with recorded NHPT and EDSS measurements at baseline, 12 months, and 24 months. This three-point longitudinal design allowed the researchers to track not just whether hand function changed, but how quickly and by how much, across a crucial two-year window that matches the duration of many phase 2 trials.

One of the study’s most important methodological contributions lies in how it defined worsening. Rather than committing to a single threshold, the investigators applied four distinct definitions of NHPT worsening: a classical definition based on overall performance, one based on the best-performing hand, one based on the worst-performing hand, and a composite definition capturing worsening in either hand, abbreviated as EH-NHPT. Each definition captures a different aspect of what clinicians and patients might consider a meaningful loss of manual dexterity, and the differences between them turned out to be substantial for trial design.

The results were striking. Across all four definitions, hand function consistently worsened over time, confirming that manual dexterity decline is a real and pervasive feature of advanced progressive multiple sclerosis rather than a statistical artifact. Under the classical, best-hand, and worst-hand definitions, approximately 25 percent of patients met the criteria for worsening at 12 months, rising to roughly 40 percent at 24 months. But the either-hand definition proved the most sensitive of all: 35.9 percent of patients showed worsening at one year, and 52.7 percent at two years. In other words, by the end of two years, more than half of this cohort had experienced a meaningful decline in the function of at least one hand—a signal strength that could dramatically reduce the sample sizes and costs of future trials.

That sensitivity came with an important caveat. Under the either-hand definition, a notable minority of patients—15.3 percent at 12 months and 9.2 percent at 24 months—showed paradoxical improvement, meaning that one hand’s performance crossed back above the threshold despite the overall trajectory of decline. This pattern reflects the inherent volatility of measuring function in a disease with fluctuating symptoms, where fatigue, temperature, spasticity, and day-to-day variation can all influence performance on a timed task. Trial designers will need to weigh the increased statistical sensitivity of the either-hand definition against the noise introduced by these apparent reversals, potentially through confirmatory re-testing protocols already common in walking-based endpoints.

The study also searched for predictors of decline, with sobering results. Logistic regression analyses of baseline characteristics found only modest associations: older age and poorer baseline hand function slightly reduced the likelihood of meeting the either-hand worsening definition at 24 months, plausibly because patients whose hands were already severely impaired had less room left to deteriorate. At the 12-month mark, no significant predictors emerged at all. The practical implication is that clinicians designing trials cannot easily pre-select patients likely to worsen rapidly; instead, the widespread and largely unpredictable nature of hand function decline in this population becomes an argument for the measure’s utility, since a high proportion of any enrolled cohort will be at risk of reaching the endpoint.

The broader context makes these findings all the more consequential. Progressive multiple sclerosis remains one of neurology’s toughest therapeutic challenges. The landmark approvals of ocrelizumab for primary progressive disease and siponimod for active secondary progressive disease marked genuine breakthroughs, but both trials enrolled predominantly ambulatory patients with lower disability scores. Meanwhile, the underlying biology of progression—inflammation within the central nervous system compartment, smouldering neurodegeneration, mitochondrial injury, and progressive gray matter atrophy—continues unchecked in people with advanced disability. Recent phase 3b work has begun to push into more advanced disease stages, and the field increasingly recognizes that the population excluded by walking-based endpoints is precisely the population with the greatest unmet need.

There is also a compelling efficiency argument. Clinical trials in progressive multiple sclerosis are notoriously expensive and slow, and the field has grappled for years with how to streamline them. A simple, cheap, chairside test of manual dexterity that can be administered in minutes without gait-dependent machinery could open trials to larger and more diverse patient populations while potentially shortening follow-up periods, given the substantial two-year event rates documented in this study. Futility-design strategies, which allow early stopping of unpromising therapies, could also benefit from the larger event rates that a sensitive hand-function endpoint provides. None of this diminishes the need for careful validation—the current study is observational, retrospective, and drawn from a single center—but it offers exactly the kind of feasibility and trajectory data that trial designers need before committing to an endpoint.

For the hundreds of thousands of people worldwide living with severe, non-ambulatory progressive multiple sclerosis, the symbolism of this research may matter as much as the statistics. A population that has effectively been told the trial system has nothing for them now has a concrete, evidence-based proposal for their inclusion, built on a test they could complete in a clinic chair in under a minute. Whether the Nine Hole Peg Test ultimately earns the status of a primary outcome measure will depend on validation in prospective, multi-center settings and on consensus among regulators and trialists. But the central question posed by the researchers—whether hand function can step up—now has a data-driven answer: hand function declines reliably in this population, the either-hand definition captures that decline more sensitively than any alternative, and the path toward more inclusive trials in progressive multiple sclerosis may well run through nine holes, nine pegs, and a stopwatch.

Subject of Research: The Nine Hole Peg Test as a potential primary outcome measure for clinical trials in non-ambulatory people with progressive multiple sclerosis

Article Title: Clinical trials in non-ambulatory people with progressive multiple sclerosis: can the nine hole peg test step up as primary outcome measure?

Article References: D’Haeseleer, M., Strijbis, E. M. M., Cutter, G., della Faille, L., D’hooghe, M. B., Kos, D., Lison, A.-L., Mostert, J., Nagels, G., Repovic, P., Uitdehaag, B. M. J., Van Remoortel, A., Van Schependom, J., & Koch, M. W. (2026). Clinical trials in non-ambulatory people with progressive multiple sclerosis: can the nine hole peg test step up as primary outcome measure?. Journal of Neurology, 273(10), Article 608. https://doi.org/10.1007/s00415-026-14140-1

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14140-1

Keywords: multiple sclerosis, progressive multiple sclerosis, Nine Hole Peg Test, hand function, non-ambulatory, clinical trials, outcome measures, EDSS, disability worsening, manual dexterity, neurology, trial endpoints