Objective: To assess clinical trial sample size estimations under variable simulated scenarios for Parkinson’s disease (PD) patients with mutations in the β-glucocerebrosidade gene (GBA1).

Background: Patients with PD show variable rates of disease progression [1]. Heterozygous mutations in the GBA1 gene, the most common genetic risk factor for PD [2], are associated with a more aggressive disease progression [3]. Understanding how PD patients carrying GBA1 mutations progress is key for planning clinical trial designs for this cohort.

Method: Data from the Parkinson’s Progression Markers Initiative (PPMI), a multicenter, longitudinal cohort study was used to design clinical trials under variable simulated scenarios regarding study duration/minimum length of follow-up, relative improvement to placebo and endpoints. Disease progression was measured with the Movement Disorder Society–Sponsored version of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts II and III.

Results: In total, 121 PD-patients with GBA mutations were included ([table1] mean age at baseline 60.8 (±9.59) years; 57.0% male, mean disease duration 2.6 (±1.77) years and mean follow-up duration 3.4 (±1.95) years). The mean change from baseline after one year was 1.6 (±3.89) and 1.9 (±10.01) for MDS-UPDRS Part II and Part III, respectively. At two years, the mean change from baseline increased to 3.1 (±4.64) and 3.9 (±12.12) for MDS-UPDRS Part II and Part III, respectively. The mean proportion of subjects getting worse by one/two years was 56%/76% and 53%/69% for MDS-UPDRS Part II and Part III, respectively. Selecting a time-to-event instead of mean change from baseline had the strongest impact on the sample size required for 80% power to detect a treatment effect (sample size reduction ≥ 78%, see [table2] for more details), followed by an increase from 30% to 50% in the relative improvement to placebo (sample size reduction ≥ 60%) and by an increase in study duration from one to two years (sample size reduction ≥ 39%).

Conclusion: The estimated progression of MDS-UPDRS scores from PPMI under various scenarios can provide valuable information for GBA-PD clinical trial planning.

References: 1. Lewis SJG, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. Heterogeneity of Parkinson’s disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005;76:343–348.
2. Siebert M, Sidransky E, Westbroek W. Glucocerebrosidase is shaking up the synucleinopathies. Brain 2014;137(pt 5):1304–1322.
3. Maple-Grødem, J., Dalen, I., Tysnes, O. B., Macleod, A. D., Forsgren, L., Counsell, C. E., & Alves, G. (2021). Association of GBA Genotype With Motor and Functional Decline in Patients With Newly Diagnosed Parkinson Disease. Neurology, 96(7), e1036–e1044.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-endpoint-selection-on-sample-size-calculations-for-disease-modifying-clinical-trials-in-parkinsons-disease-patients-with-gba1-mutations/