Long-Term Clinical Efficacy, Safety, and Polypharmacy Simplification of Levodopa–Entacapone–Carbidopa Intestinal Gel in Advanced Parkinson’s Disease: An 18-Month Longitudinal Study

Background: Advanced Parkinson’s disease (aPD) is characterized by motor fluctuations, unpredictable oral absorption, and severe dyskinesias. Levodopa–entacapone–carbidopa intestinal gel (LECIG) is designed to provide dopaminergic stimulation and optimize levodopa bioavailability. We evaluated 18-month clinical outcomes, motor stabilization, disease burden, and oral medication simplification in a real-world cohort transitioning to LECIG. Methods: This retrospective longitudinal study included 41 patients with medication-refractory aPD. Patients underwent nasojejunal titration (mean 5.58 ± 1.50 days), followed by percutaneous endoscopic gastrojejunostomy. Assessments were performed at baseline, initiation, and 6, 12, and 18 months. Primary endpoints were daily OFF time, dyskinesia duration, and non-linear fluctuations. Disease burden was analyzed using Linear Mixed-Effects Models and medication changes using McNemar tests and paired t-tests. Results: Patients (56.1% male; mean age 65.39 ± 8.32 years; disease duration 10.46 ± 4.23 years) demonstrated significant and sustained clinical improvements. For the 38 patients evaluable at 18 months, daily OFF time decreased from 4.67 ± 0.79 h to 1.34 ± 0.40 at initiation and 1.55 ± 0.69 at 18 months (p < 0.0001; 66.8% reduction). Severe peak-dose dyskinesia was absent after initiation (2.17 ± 1.00 to 0.00 h/day; p < 0.001), whereas early morning akinesia decreased from 78.0% to 36.6% and freezing of gait from 56.1% to 31.6%. Total Clinical Burden Score decreased from 9.33 to 3.49 (−62.6%). Dopamine agonist use decreased from 80.5% to 42.1% at 18 months (McNemar p < 0.0001), while adjunct medications decreased from 1.73 to 1.39/patient (p = 0.0284). Adverse events were predominantly mild-to-moderate. No patient discontinued therapy because of an adverse event or hardware failure; one patient discontinued LECIG by personal choice. Two additional patients died from sudden cardiac arrest during follow-up, both considered unrelated to LECIG therapy or pump hardware. At 18 months, 38 of 41 patients remained evaluable. Conclusions: In this observational cohort, LECIG initiation was followed by sustained reductions in motor complications, OFF time, and clinical burden over 18 months. Treatment was also associated with a reduction in dopamine agonist use and overall adjunctive medication burden. The favorable tolerability and low discontinuation rate observed support further evaluation of LECIG as an advanced treatment pathway. However, pre-switch LEDD calculations may support initial pump programming but should not be considered definitive predictors of individualized maintenance settings; inpatient clinical titration remains necessary.