Objective: To provide the methodological rationale for using a time-to-event (TTE) primary endpoint in the PADOVA study.

Background: The use of symptomatic medications represents a challenge for clinical trials of novel medicines designed to slow Parkinson’s disease (PD) progression. A TTE approach may offer an alternative to the traditional change from baseline approach in PD clinical trials.

Method: The Phase IIb PADOVA study (NCT04777331) evaluated the efficacy, safety and pharmacokinetics of prasinezumab in participants with early-stage PD on stable monoamine oxidase type B inhibitor or levodopa monotherapy for ≥3 months prior to randomization. The primary endpoint was time to confirmed motor progression, defined as ≥5-points increase from baseline on MDS-UPDRS Part III in OFF-medication state. The TTE threshold of 5 points was estimated via an anchor-based analysis and supported by expert consensus for use as an indicator of meaningful motor progression [1]. The TTE approach was selected to mitigate the potential masking effect of changes made to participants’ symptomatic medication.

Results: Prasinezumab showed a trend toward clinical benefit with a hazard ratio of 0.84 (95% confidence interval [CI]: 0.69, 1.01) and a p-value of 0.0657. When the change in motor function (MDS-UPDRS Part III in OFF medication) was analyzed using a mixed model for repeated measures (MMRM), there was no difference between the prasinezumab and placebo groups at Week 76. At the end of the double-blind period, 56% (326/586) of participants had been treated for 104 weeks. In this subset, the MMRM model showed a numerical difference (~35% relative reduction) favoring prasinezumab (difference in adjusted means, -2.18 [95% CI: -3.87, -0.49]; nominal p-value = 0.0117).

Conclusion: Insights from the PADOVA study provide important evidence to support validation of the use of a TTE approach in early-stage PD for future clinical trials. This methodology can capture the benefits of new treatments in a reasonable timeframe and allows for precise and meaningful measurement of treatment effect.

References: Trundell D, Davies EW, Barrett L, et al. Estimation of and clinical consensus on the meaningful motor progression threshold on MDS-UPDRS Part III. J Parkinsons Dis. 2025 Jan 14:1877718X241302337 [online ahead of print].

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MDS Abstracts - https://www.mdsabstracts.org/abstract/methodological-considerations-supporting-a-time-to-event-primary-endpoint-in-the-padova-study-in-early-stage-parkinsons-disease-participants-on-stable-symptomatic-treatment/