Levodopa‐Carbidopa Intestinal Gel in an Outpatient Setting: A 10‐Year Experience

Levodopa-Carbidopa Intestinal Gel (LCIG) is an effective therapy for advanced Parkinson's Disease (PD), initiated in hospitalized patients. Inpatient care is associated with complications, including infections and confusion.1 In 2015, we published our initial experience of LCIG in an outpatient-only setting with promising results in five patients.2 A decade later, we retrospectively studied all the patients treated in our center utilizing this model. All PD patients who underwent percutaneous endoscopic gastrojejunostomy (PEG-J) placement for LCIG delivery from March 2015 until February 2024 were included. Motor severity was evaluated using part III of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS III), while anti-PD medications and LCIG infusion parameters were measured as Levodopa Equivalent Daily Dose (LEDD). Clinical data were collected at: T0 (peri-operative), T1 (6–12 months after LCIG initiation), and T2 (latest follow-up). The average time between PEG-J placement and LCIG initiation was 15 days. Baseline, 12-month, and 24-month levels of vitamin B6, B12, homocysteine, and methylmalonic acid (MMA) were measured. Adverse events (AEs) were categorized into seven subgroups and deemed severe (SAEs) if resulting in death, hospitalization, or LCIG discontinuation. Premature discontinuation rate (not caused by patient's death) and mortality were also assessed. Eighty consecutive patients (29 females, 36.3%) with a mean age of 75.3 ± 8.9 years (range 31–93) and disease duration of 18.3 ± 6.7 years (range 5–42) were included. A NJ tube test was adopted in 7 of the 72 cases (8.8%). LCIG treatment duration was 4.6 ± 2.8 (0.5–13) years. A premature LCIG discontinuation occurred in 7 cases (8.6%, Fig. 1A) due to disabling dyskinesias (2); gastrointestinal/stoma issues (2); long-term facility management difficulties (2); interference with patient's lifestyle (1). No significant difference in total LEDD or MDS-UPDRS-III ON levodopa was found over time (repeated measures ANOVA, Fig. 1B,C). Other anti-PD drugs decreased over time (Fig. 1D) except for bedtime oral levodopa, slightly reduced (T0: n = 57 [77%]; T1: n = 48 [70%]; T2: n = 45 [65.2%]). At the latest follow-up, 24 h-LCIG was administrated in 14 cases (20%) to manage sleep issues and/or biphasic dyskinesias. LCIG and related procedures were well tolerated. One death due to a possible cardiac event occurred peri-operatively, with no other major complications. Vitamin B6 and B12 were found to be decreased (and supplemented) in 20/34 (58.8%) and 19/37 (51.3%) of patients, so that average plasma levels were kept within the normal range (Fig. 1G,F). Thirty-two (40%) patients died at last follow up (Fig. 1E), mainly from worsening general conditions (15) and COVID-19 pneumonia (6). AEs incidence over time is shown in Figure 1H. All the SAEs and AEs are shown in Supplementary Table S1. This is the first long-term retrospective study of LCIG initiation and management in an outpatient-only setting. AEs and SAEs were consistent with inpatient LCIG initiation studies.3, 4 Mortality was high but unrelated to LCIG and discontinuation rate was low (8.6%). Over time, anti-PD medication use decreased.5 Vitamin B deficiencies and polyneuropathy risks were managed with monitoring and supplementation, resulting in a low 5.0% polyneuropathy rate. Most AEs occurred in the first year and rarely led to discontinuation. Few patients experienced AEs immediately post-implantation. Over time, disease progression-related AEs, such as dyskinesias and behavioral issues, increased but were rarely severe.3, 4 The limitations of this study include retrospective design and lack of an inpatient comparison group. Nevertheless, LCIG initiation in an outpatient setting seems to be safe, cost-effective, and well-accepted by patients and families. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. A.M.: 1A, 2A, 2B, 2C, 3A, 3B. N.F.: 1A, 1B, 1C, 2C, 3B. Y.Y.P.: 1A, 1B, 1C, 2C, 3B. T.N.: 1A, 1B, 1C, 2C, 3B. L.L.: 1A, 1B, 1C, 2C, 3B. Y.T.: 1A, 1B, 1C, 2C, 3B. A.E.L.: 1A, 1B, 1C, 2C, 3B. A.F.: 1A, 1B, 1C, 2A, 2C, 3B. Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. This retrospective study was approved by the local ethics committee and performed in accordance with the declaration of Helsinki. Informed patient consent was not necessary for this retrospective work. Founding Sources and Conflict of Interest: This study was partly funded by the University of Toronto and University Health Network Chair in Neuromodulation to AF. AF has stock ownership in Inbrain Pharma and has received payments as consultant and/or speaker from Abbvie, Abbott, Boston Scientific, Ceregate, Dompé Farmaceutici, Inbrain Neuroelectronics, Ipsen, Medtronic, Iota, Syneos Health, Merz, Sunovion, Paladin Labs, UCB, Sunovion. He has received research support from Abbvie, Boston Scientific, Medtronic, Praxis, ES and receives royalties from Springer. AEL has served as an advisor for AbbVie, Amylyx, Aprinoia, Biogen, BioAdvance, Biohaven, BioVie, BlueRock, BMS, Denali, Janssen, Lilly, Pharma 2B, Sun Pharma, and UCB; received honoraria from Sun Pharma, AbbVie and Sunovion; received grants from Brain Canada, Canadian Institutes of Health Research, Edmond J. Safra Philanthropic Foundation, Michael J. Fox Foundation, Parkinson Foundation, and Parkinson Canada, is serving as an expert witness in litigation related to paraquat and Parkinson's disease, received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. Other authors have no additional conflicts of interest. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. The data that support the findings of this study are available from the corresponding author upon reasonable request. TABLE S1. Number of total adverse events (AEs) and serious adverse events (SAEs) reported among the 80 consecutive LCIG patients included in the study. Values are N (%) of 234 AEs and 26 SAEs. * Vitamin B6 range: 20–96 nmol/L, **Vitamin B12 range: 222–652 pmol/L, *** Anemia: 3 (27.3%); brain hemorrhage: 2 (18.2%), hip fracture: 2 (18.2%), pancreatic cancer: 1 (9.1%); delirium 2: (18.2%), possible cardiac event: 1 (9.1%). 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