The study, led by Andrew McGarry of Clintrex Research Corporation and Cooper Medical School at Rowan University, together with colleagues at ABLi Therapeutics and the University of Rochester School of Medicine, applied time-to-event methodology, a statistical framework borrowed from fields such as oncology and cardiology, to data from four early interventional studies and one observational cohort in early, untreated Parkinson’s disease. Rather than comparing average score changes between groups, time-to-event analysis asks a simpler and arguably more clinically resonant question: how long does it take before a patient experiences a defined amount of worsening, and what proportion of patients reach that threshold within a given period?

The technical appeal of this approach is substantial. Traditional endpoints in Parkinson’s trials typically rely on mean changes in scores on the Unified Parkinson’s Disease Rating Scale, or its modern revision, the Movement Disorders Society version known as the MDS-UPDRS. Mean-change endpoints can be diluted by patients who improve slightly, stay stable, or fluctuate for reasons unrelated to the disease process, and they are vulnerable to confounding the moment a participant begins dopaminergic treatment, which can mask underlying progression. A time-to-event endpoint, by contrast, focuses on the first time a participant crosses a pre-specified worsening threshold, an event that is binary, interpretable, and directly tied to something a clinician and patient can recognize as real deterioration.

In this analysis, the researchers examined two complementary dimensions of the disease. Part 3 of the MDS-UPDRS captures the motor examination, the tremor, rigidity, slowness, and gait changes that a clinician observes during a structured assessment. Part 2 captures the patient’s own report of functional experiences in daily life, such as difficulty with dressing, eating, handwriting, and walking. The team asked how many participants, while remaining untreated over a 12-month period, crossed worsening thresholds of varying magnitudes on each of these scales, and whether crossing a motor examination threshold was accompanied by concurrent functional decline.

The headline finding concerns the feasibility of demanding large, clinically meaningful changes. At the most stringent thresholds examined, between 32 and 42 percent of participants across the cohorts reached a worsening of at least 4 points on Part 2 within 12 months, while between 27 and 34 percent reached a worsening of at least 7 points on Part 3. Those proportions may sound modest, but in trial-design terms they are consequential. A trial powered on an event rate of roughly one in three participants over a year is a very different, and far more achievable, proposition than one requiring the majority of participants to deteriorate substantially before any signal can emerge.

As the thresholds were relaxed, the picture changed predictably. Lowering the bar for what counts as worsening increased the proportion of participants achieving it in every cohort analyzed, a consistent dose-response-like relationship between threshold stringency and event frequency. This gradient gives trial designers a tunable dial: a sponsor can choose a threshold that is clinically defensible and simultaneously yields enough events within the planned follow-up to give the study adequate statistical power. The analysis suggests that 12-month studies powered for large worsening thresholds in motor examination scores are genuinely feasible in early Parkinson’s disease, a conclusion that could influence how the next generation of disease-modification trials is designed.

Perhaps the most clinically important finding is the coupling between the motor examination and daily function. Many participants who crossed each Part 3 threshold experienced simultaneous worsening on Part 2, and higher motor examination thresholds were generally associated with greater functional worsening. In plain terms, when the examiner’s findings deteriorated by a meaningful amount, the patient’s lived experience deteriorated too. This linkage matters because it addresses a persistent criticism of rating-scale endpoints: that a few points on a clinician’s checklist might not translate into anything a patient actually feels. Here, the motor examination thresholds were anchored to concurrent functional decline, strengthening the argument that these are not arbitrary statistical constructs but markers of genuine clinical change.

The confounding problem that motivated the work deserves emphasis. In early Parkinson’s disease, the standard of care is to begin symptomatic treatment, typically levodopa or a dopamine agonist, when symptoms begin to interfere with daily life. Once treatment starts, the underlying disease trajectory becomes obscured, because dopaminergic medication improves motor scores regardless of whether the disease itself has slowed. A trial that allows treatment initiation partway through risks comparing groups in which different proportions of participants have started medication, contaminating the endpoint. Time-to-event analyses that focus on the untreated period, as this study does, sidestep much of that contamination by capturing progression before the therapeutic veil descends, and by treating treatment initiation itself as a censoring event or a competing consideration in the analysis.

The study drew on data from both interventional trials and the Parkinson’s Progression Markers Initiative, the large observational study funded by the Michael J. Fox Foundation for Parkinson’s Research and its partners. Combining randomized trial cohorts with a naturalistic observational cohort is a strength, because it tests whether the event rates are reproducible across different settings, populations, and assessment practices. The consistency of the pattern, with proportions of untreated worsening rising as thresholds relaxed in all cohorts, suggests that the findings are not an artifact of any single study’s design or population. The work was funded by ABLi Therapeutics, and the authors declared no competing interests in the published report.

For the field, the implications point toward a practical redesign of early-phase disease-modification trials. Sponsors evaluating candidate therapies in newly diagnosed, untreated patients can now consider endpoints built on time to a large, clinically anchored worsening event, with realistic expectations about event rates over 12 months and a defensible link between the motor examination and patients’ daily functioning. That could mean smaller trials, shorter trials, or trials with a clearer path to demonstrating benefit that regulators, clinicians, and patients can all interpret in the same way. It is a reminder that sometimes the most powerful question in medicine is not how much a patient changed, but how long it took for the change to become undeniable.

Subject of Research: Time-to-event analysis of motor and functional outcomes in early untreated Parkinson's disease clinical trials

Article Title: Time-to-event analyses of motor examination and functional outcomes in early Parkinson’s disease clinical trials

Article References: McGarry, A., Meyer, C. R., Kieburtz, K., Dubow, J., Werner, M. H., & Venuto, C. (2026). Time-to-event analyses of motor examination and functional outcomes in early Parkinson’s disease clinical trials. npj Parkinson's Disease. https://doi.org/10.1038/s41531-026-01578-3

Image Credits: AI Generated

DOI: 10.1038/s41531-026-01578-3

Keywords: Parkinson's disease, time-to-event analysis, clinical trials, MDS-UPDRS, motor progression, disease-modifying therapy, clinical endpoints, neurology, observational study, PPMI, untreated patients, functional outcomes