Factors Associated with Early Discontinuation of Foslevodopa/Foscarbidopa in Parkinson's Disease

Continuous subcutaneous infusion of foslevodopa/foscarbidopa (CSFLI) is a device-aided therapy designed to stabilize dopamine delivery and reduce motor and non-motor fluctuations in Parkinson's disease (PD).1 Despite proven efficacy in clinical trials,2, 3 early discontinuation rates, mainly due to adverse events, remain a clinical concern. To better understand the factors associated with early discontinuation, we conducted a single-center prospective cohort study of consecutive patients with advanced PD who initiated CSFLI therapy at the University of Osaka Hospital between July 2023 and January 2025. All participants underwent a standardized 3-week inpatient initiation protocol (Methods S1). Patients were followed for 3 months, and early discontinuation, defined as discontinuation within this period, was evaluated as the primary outcome. Patients were classified into continuation and discontinuation groups, and their baseline characteristics, treatment adjustments, and adverse events were compared. Troublesome dyskinesia was defined as dyskinesia with significant functional impact (MDS-UPDRS Part IV-1 ≥ 2 and IV-2 ≥ 2, or IV-2 ≥ 3). A total of 20 consecutive patients were enrolled, and six (30%) discontinued CSFLI within 3 months (Table 1 and S1). The reasons for discontinuation included insufficient improvement in motor fluctuations (n = 3), difficulty in handling the device (n = 3), psychosis (n = 2), worsening of dyskinesia (n = 2), and infusion site infection (n = 1), with some patients reporting multiple causes. The average time to discontinuation was 13.1 ± 9.9 days (mean ± standard deviation). The discontinuation group had significantly higher baseline levodopa equivalent daily dose (LEDD)4 than the continuation group (1640 ± 291 vs 1303 ± 322 mg/day; p < 0.05) and tended to be older with greater cognitive impairment (lower MoCA scores) and more severe autonomic dysfunction (higher SCOPA-AUT scores) (Table 1). Baseline troublesome dyskinesia was observed exclusively in the continuation group and improved after CSFLI initiation, whereas dyskinesia worsened in three patients in the discontinuation group. Among the adverse events during the follow-up period, worsening of dyskinesia and difficulty in handling the device were more frequent in the discontinuation group (Table 1). Subcutaneous induration occurred more often in the continuation group, which likely reflects a longer treatment duration. In the discontinuation group, LEDD increased rapidly within the first week in response to insufficient improvement of motor symptoms (Fig. S1), through escalation of CSFLI flow rates or reintroduction of opicapone, whereas similar adjustments were applied after 2 weeks in the continuation group (Table S2). These findings suggest that rapid escalation of CSFLI flow rates or reintroduction of opicapone requires caution, particularly during the first week after CSFLI initiation. In summary, high baseline LEDD, rapid dose escalation, and worsening dyskinesia were associated with early discontinuation, whereas improvement in troublesome dyskinesia was correlated with treatment continuation. Interestingly, previous studies have reported the opposite trend, with higher pre-CSFLI LEDD in patients who continued treatment than in those who discontinued5; however, the LEDD in their continuation group was comparable to that of our continuation group. These divergent findings may reflect differences in patient selection and suggest that an optimal LEDD range for successful CSFLI initiation may exist. The contrasting findings—improvement in troublesome dyskinesia in the continuation group and worsening in the discontinuation group—suggest that the therapeutic benefits may contribute to patient motivation to continue CSFLI. These observations highlight the need for careful dopaminergic titration, individualized dose adjustments, and cautious use of COMT inhibitors during CSFLI initiation, particularly in older patients with advanced disease, as in our cohort. In this study, however, statistical tests were exploratory and unadjusted for multiple comparisons due to a small sample size. Further validation in larger multicenter studies is warranted. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. K.K: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B. Y.K: 1A, 1B, 1C, 2C, 3B. L.G: 1C, 2B, 3C. K.I: 1C, 3B. K.A: 1C, 3B. S.M: 1C, 3B. K.O: 1C, 3B. H.M: 1A, 1B, 3C. We sincerely thank all patients and their families for their participation and invaluable cooperation in this study. We also express our deep gratitude to the medical staff of the University of Osaka Hospital for their dedicated care and support during the hospital stay. Ethical Compliance Statement: The study protocol adhered to the principles outlined in the Declaration of Helsinki and was approved by the University of Osaka Review Board (approval numbers 13,471 and 22,311). Written informed consent was obtained from all patients. We confirm that we have read the Journal's guidelines on issues involved in ethical publication and affirm that this work is consistent with these guidelines. Funding Sources and Conflict of Interest: No specific funding was received for the study. The authors declare no conflicts of interest relevant to this study. Financial Disclosures for the previous 12 months: K.K. reports honoraria from Ono Pharm Co., Ltd. and FP Co., Ltd. and a grant from the Grants-in-Aid for Scientific Research and the Japan Agency for Medical Research and Development. Y.K. reports honoraria from AbbVie Inc.; Eisai Co., Ltd.; FP Co., Ltd.; Ono Pharm Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; TEIJIN HOME HEALTHCARE Ltd.; Viatris Inc.; Grants-in-Aid for Scientific Research; and the Japan Agency for Medical Research and Development. K.I. reports honoraria from Eisai Co., Ltd., FP Co., Ltd., AbbVie Inc., Grants-in-Aid for Scientific Research, and the Japan Agency for Medical Research and Development. K.O. reports honoraria from Ono Pharm Co., Ltd. and a grant from the Grants-in-Aid for Scientific Research, Takeda Research Foundation, and Japan Agency for Medical Research and Development. H.M. reports honoraria from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., AbbVie Inc., Eli Lilly Japan K. K, Shionogi & Co., Ltd., Rikaken Co., Ltd., T-PEC, GlobalData Plc, Guidepoint Global, LLC., and K Pharma, Inc. and grants from Grants-in-Aid for Scientific Research, Health Labour Sciences Research Grant, and the Japan Agency for Medical Research and Development. L.G., K.A., and S.M. report no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Methods S1. Structured Inpatient Protocol for CSFLI Initiation. Description of a standardized 3-week inpatient protocol used for CSFLI initiation, including baseline assessments, inpatient titration and troubleshooting, patient education, and post-discharge care planning. Table S1. Details of Each Discontinuation Case. Detailed baseline characteristics, reasons for discontinuation, clinical courses leading to discontinuation, and treatment parameters of patients who discontinued CSFLI. Figure S1. Transition of total levodopa equivalent daily dose from before initiation of continuous subcutaneous infusion of foslevodopa/foscarbidopa to 1 week after the initiation. Transition of LEDD from before initiation (Pre) to 1 week (1w) after initiation in the continuation and discontinuation groups. Two-way analysis of variance, ***p < 0.0001, continuation versus discontinuation groups. Error bars: standard error. Table S2. Drug dosage in each group before and after the initiation of continuous subcutaneous infusion of foslevodopa/foscarbidopa. The average total LEDD, daytime and nighttime CSFLI flow rates, dopamine agonist LEDD, MAOB-I LEDD, and the number and percentage of opicapone users in the continuation and discontinuation groups are shown at each time point. Comparisons between the two groups were performed using the Student's t-test for each LEDD and the chi-square test for opicapone usage. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.