Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson's disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial.

BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete. FINDINGS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). INTERPRETATION: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. FUNDING: NeuroDerm.

Levodopa-Entacapone-Carbidopa Intestinal Gel Treatment in Advanced Parkinson's Disease: A Single-Center Study of 30 Patients.

BACKGROUND: Levodopa-entacapone-carbidopa intestinal gel (LECIG) is a novel device assisted treatment option for advanced Parkinson's disease (PD). It has been available in Finland since 2020. There is paucity of scientific studies considering LECIG treatment in clinical practice. OBJECTIVES: Objectives of this study were to evaluate the changes in medication, adverse events and early discontinuations of LECIG treatment in real life clinical practice. METHODS: The records of 30 consecutive patients, who received LECIG between years 2020 and 2022 in Helsinki University Hospital, were retrospectively analyzed. Data considering changes in medication, discontinuations, and adverse events during the first six months of LECIG treatment was collected. RESULTS: Mean levodopa equivalent daily dose (LEDD) rose significantly between baseline before LECIG and six months with treatment (1230 mg vs. 1570 mg, P = 0.001). Three patients were discarded during nasojejunal tube test phase and seven discontinued the treatment during six-month follow-up. Most common reasons for discontinuation were difficulty in finding suitable infusion rate and neuropsychiatric problems. Safety issues encountered were similar to those reported with levodopa-carbidopa intestinal gel (LCIG) treatment. One case of rhabdomyolysis due to severe dyskinesia during LECIG treatment was observed. Patients were satisfied with the small size of the pump system. CONCLUSIONS: LEDD seems to increase during the first months of LECIG treatment. When compared to studies on LCIG, safety profile of LECIG appears similar, but early discontinuation rate is higher than expected. However, long-term studies are lacking. Only clear advantage to LCIG appears to be the smaller LECIG pump size.

Reduced Plasma Levodopa Fluctuations with More Frequent Administration of a Novel Carbidopa/Levodopa Functionally Scored Tablet.

Levodopa/carbidopa remains the gold standard for treating Parkinson disease (PD), but chronic pulsatile administration contributes to motor complications. This Phase 1 study used a new immediate-release (IR) formulation of carbidopa/levodopa 25/100 mg that is functionally scored for easy and precise splitting to evaluate the effects on levodopa plasma variability when smaller doses are taken more frequently. These functionally scored tablets were shown to be bioequivalent to carbidopa/levodopa 25-/100-mg IR generic reference tablets. Twenty-two healthy volunteers received a whole tablet every 4 hours versus half of the tablet every 2 hours. Plasma levodopa fluctuations were significantly reduced with half-tablets dosed every 2 hours, with a 44% reduction in peaks (P < .0001). While drug exposure did not differ, parameters that underlie motor response variations, including mean peak-to-trough difference and variance, were 51% and 56% less, respectively, with more frequent dosing (both P ≤ .0024). Safety and tolerability of both regimens were similar. In conclusion, more frequent administration of half-tablets of the new functionally scored IR formulation safely provided more constant levodopa levels than whole tablets dosed less often. This tablet technology could facilitate the benefits of more physiologic dopamine replenishment in patients with PD, particularly those with reduced manual dexterity.

Weight loss in Parkinson's disease: A retrospective comparison between oral medication and device-assisted therapies.

OBJECTIVE: Weight loss (WL) is the most common symptom among patients with Parkinson's disease (PD) and has been reported to start several years before the diagnosis of PD. The relationship between WL and PD treatment is complex. This study aimed to characterize the impact of PD treatment on WL and find clues to establish the administration of nutrition for patients with PD. MATERIALS AND METHODS: Eighty-two patients with PD (mean age, 58.4 ± 10.2 years; mean Hoehn and Yahr stage, 3.2 ± 0.7) were recruited. Their treatments included deep brain stimulation (DBS) therapy (n = 34), levodopa/carbidopa intestinal gel (LCIG) therapy (n = 13), and oral medication alone (n = 35). Based on the medical records, the age of onset, disease duration, treatment options, videofluoroscopic dysphagia scale, blood test results, and weight change were collected. RESULTS: The median WL per year and rate of WL were -1.0 ± 2.8 kg and -1.9 ± 4.7 %, respectively. Most patients (93 %) were classified into normal nutrition and mild malnutrition groups by their CONUT scores. The median WL of the DBS group was significantly lower than that of the oral medication alone group (p < 0.01). The rate of WL showed a significant negative correlation with the age of onset (rho = -0.328, p = 0.003), but showed a significant positive correlation with the disease duration (rho = 0.231, p = 0.04). CONCLUSION: These results highlighted WL in the early stages of PD and suggested the need for adequate monitoring for patients undergoing device-aided therapy as well as oral medicine-treated patients with greater WL.

Safety and Efficacy of IPX203 in Parkinson's Disease: The RISE-PD Open-Label Extension Study.

BACKGROUND: IPX203 is a novel oral extended-release formulation of carbidopa/levodopa (CD/LD) developed to address the short half-life of immediate-release CD/LD. In the phase 3 RISE-PD trial, IPX203 significantly improved "Good On" time in patients with Parkinson's disease compared with immediate-release CD/LD. OBJECTIVES: To evaluate the safety and efficacy of IPX203 in an open-label extension of the pivotal phase 3 study. METHODS: This 9-month extension enrolled patients who completed the randomized, double-blind trial. Key efficacy endpoints included Movement Disorder Society-Unified Parkinson's Disease Rating Scale and Patient and Clinical Global Impression scores. Adverse events (AEs) were recorded. RESULTS: Improvements in efficacy were maintained and dosing frequency and total daily dose remained stable through the trial. A total of 52.7% of patients experienced ≥1 treatment-emergent AE, mostly mild or moderate and occurred within the first 90 days of treatment. CONCLUSIONS: In this phase 3 open-label extension, IPX203 exhibited a favorable safety and tolerability profile and sustained efficacy of comparable magnitude to the end of the double-blind study. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Continuous subcutaneous levodopa-carbidopa for the treatment of advanced Parkinson's disease: is it an improvement on other delivery?

INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disease and is growing in prevalence and disability. The standard treatment for PD is oral levo-dopa (LD) with carbidopa (CD). As PD progresses, despite higher doses of LD/CD, plasma levels of LD fluctuate, and may be associated with motor fluctuations and dyskinesia. AREAS COVERED: The development of two new subcutaneous preparations of LD/CD (ND0612 and ABBV-951) for the treatment of motor fluctuations in PD is described in detail. Both reduce motor fluctuations and dyskinesia with minor infusion site adverse events. A third subcutaneous preparation, DIZ102, is in early-stage development. EXPERT OPINION: The premise for using continuous release LD in advanced PD is that steady state levels of LD will prevent motor fluctuations/dyskinesia, but this is not the whole story, and will limit the benefits of subcutaneous continuous release LD. With its present pump system ND0612 cannot be used as monotherapy, whereas ABBV-951 can be. Having to combine with oral LD/CD will complicate the use of ND0612. Both ND0612 and ABBV-951 only cause modest reductions in OFF time. It is not clear whether these subcutaneous preparations will have more benefits than the intestinal gel, which also reduces OFF time and dyskinesia.

Levodopa/Carbidopa to Augment the Treatment of Amblyopia: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the published literature on the use of levodopa/carbidopa to augment the treatment of amblyopia. METHODS: Literature searches for English language studies were last conducted in October 2022 in the PubMed database with no date restrictions. The combined searches yielded 55 articles, of which 23 were reviewed in full text. Twelve of these were considered appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. Nine studies were rated level I, and 3 studies were rated level II; there were no level III studies. RESULTS: The duration of treatment was limited to 3 to 16 weeks because of concern about long-term adverse effects such as tardive dyskinesia. This complication was not reported in any of the study participants. The dose of levodopa ranged from 1.5 to 8.3 mg/kg/day, generally divided into 3 daily doses. The carbidopa dose was approximately 25% of the levodopa dose in all treatments. Evidence from these studies indicates that augmenting traditional patch occlusion therapy with the oral administration of levodopa/carbidopa can improve the vision of amblyopic children, but the effect was small (0.17-0.3 logarithm of the minimum angle of resolution [logMAR] units) and only statistically significant when compared with patching alone in 2 of the 12 studies cited. Regression of vision was reported in the majority of studies (9 of 12 reported; range, 0-0.17 logMAR unit regression) after discontinuation of therapy. Short-term side effects of the medications were not consistently reported but were most frequently mild and included headache and nausea. CONCLUSIONS: The best available evidence is currently insufficient to show that augmenting amblyopia therapy using up to 16 weeks of levodopa/carbidopa will result in meaningful improvement in visual acuity. Given the potential for significant side effects such as tardive dyskinesia with long-term therapy, levodopa/carbidopa does not appear to be a viable option for amblyopia therapy FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Levodopa Carbidopa Intestinal Gel in Advanced Parkinson's Disease: DUOGLOBE Final 3-Year Results.

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) improves motor and non-motor symptoms in patients with advanced Parkinson's disease (aPD). OBJECTIVE: To present the final 36-month efficacy and safety results from DUOGLOBE (DUOdopa/Duopa in Patients with Advanced Parkinson's Disease - a GLobal OBservational Study Evaluating Long-Term Effectiveness; NCT02611713). METHODS: DUOGLOBE was an international, prospective, long-term, real-world, observational study of patients with aPD initiating LCIG in routine clinical care. The primary endpoint was change in patient-reported "Off" time to Month 36. Safety was assessed by monitoring serious adverse events (SAEs). RESULTS: Significant improvements in "Off" time were maintained over 3 years (mean [SD]: -3.3 hours [3.7]; p < 0.001). There were significant improvements to Month 36 in total scores of the Unified Dyskinesia Rating Scale (-5.9 [23.7]; p = 0.044), Non-Motor Symptoms Scale (-14.3 [40.5]; p = 0.002), Parkinson's Disease Sleep Scale-2 (-5.8 [12.9]; p < 0.001), and Epworth Sleepiness Scale (-1.8 [6.0]; p = 0.008). Health-related quality of life and caregiver burden significantly improved through Months 24 and 30, respectively (Month 24, 8-item Parkinson's Disease Questionnaire Summary Index, -6.0 [22.5]; p = 0.006; Month 30, Modified Caregiver Strain Index, -2.3 [7.6]; p = 0.026). Safety was consistent with the well-established LCIG profile (SAEs: 54.9% of patients; discontinuations: 54.4%; discontinuations due to an adverse event: 27.2%). Of 106 study discontinuations, 32 patients (30.2%) continued LCIG outside the study. CONCLUSION: DUOGLOBE demonstrates real-world, long-term, reductions in motor and non-motor symptoms in patients with aPD treated with LCIG.

The impact of dysphagia in Parkinson's disease patients treated with levodopa/carbidopa intestinal gel.

BACKGROUND: Dysphagia is common in advanced phases of Parkinson disease (PD), and is a risk factor for aspiration pneumonia. Nonetheless, dysphagia has been poorly investigated in PD patients treated with levodopa-carbidopa intestinal gel (LCIG). We aimed to analyze the impact of dysphagia on mortality in LCIG treated patients and its relationship with other PD disability milestones. METHODS: We retrospectively evaluated 95 consecutive PD patients treated with LCIG. Kaplan-Meier and log-rank test were used to compare mortality in patients with dysphagia from others. Cox regression was used to estimate the impact of dysphagia, age, disease duration, and Hoehn and Yahr (H&Y) on mortality in the entire cohort. Finally, univariate and multivariate regression analyses were used to estimate the association between dysphagia and age, disease duration, H&Y, hallucinations, and dementia. RESULTS: A significantly higher mortality rate was observed in patients with dysphagia. In the Cox model, dysphagia was the only feature significantly associated with mortality (95%CI 2.780-20.609; p < 0.001). Univariate analyses showed a significant correlation between dysphagia and dementia (OR: 0.387; p:0.033), hallucinations (OR: 0.283; p:0.009), and H&Y score (OR: 2.680; p < 0.001); in the multivariate analysis, only the H&Y stage was associated with the presence of dysphagia (OR: 2.357; p:0.003). CONCLUSION: Dysphagia significantly increased the risk of death in our cohort of LCIG-treated patients, independently from other relevant features such as age, disease duration, dementia, and hallucinations. These findings support the management of this symptom as a priority in the advanced PD stages, even in people treated with LCIG.

Long-Duration Response to Levodopa, Motor Learning, and Neuroplasticity in Early Parkinson's Disease.

BACKGROUND: Long-duration response (LDR) to levodopa and motor learning could be involved in changes in neuroplasticity of cortical excitability in Parkinson's disease (PD). P300, motor evoked potentials (MEPs), and Bereitschaftspotential (BP) are neurophysiological surrogate markers of neuroplasticity. OBJECTIVE: We aimed to define in PD the effects of LDR and motor learning on neurophysiological parameters involved in neuroplasticity. METHODS: Drug-naive PD patients underwent a 15-day treatment with levodopa/carbidopa 250/25 mg daily. Achievement of LDR was assessed on the 15th day of treatment (T15). Patients were grouped based on the achievement of a sustained LDR (LDR+) or no LDR (LDR-) and to the assignment of a learning motor exercise (LME) or no motor exercise (NME). Patients underwent clinical and neurophysiological (P300, MEPs, and BP) assessments at baseline (T0) and on T15. RESULTS: Forty-one PD patients and 24 age- and sex-matched normal controls (NCs) were enrolled. Neurophysiological parameters differed between untreated PD patients and NCs. Four groups of patients were obtained at the end of treatments: trained patients with a sustained LDR (LDR + LME group), untrained patients with a sustained LDR (LDR + NME group), trained patients without LDR (LDR-LME group), and untrained patients without LDR (LDR-NME group). At baseline, no differences in clinical and neurophysiological parameters were evident among the groups. After the treatments, significant improvements in neurophysiological parameters were observed in the LDR + LME group. No modifications were found in the groups without LDR. CONCLUSIONS: The achievement of a sustained LDR may act synergistically with motor learning to induce adaptive changes in neuroplasticity in basal ganglia and cortical networks. Our findings support LDR as a pharmacological outcome possibly facilitating the action of motor learning on neuroplasticity in early PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Acute/subacutae demyelinating polyneuropathy in Parkinson's Disease patients on levodopa-carbidopa intestinal gel therapy: systematic review with new case report.

Polyneuropathy (PNP) is a known complication of levodopa-carbidopa intestinal gel (LCIG) therapy of advanced Parkinson's Disease (PD). The overall prevalence of PNP in PD is estimated to be 42.1% (as shown in a review by Romagnolo et al. 2018), and the most common type is chronic axonal polyneuropathy. There is a group of acute/subacute onset demyelinating polyneuropathies, which is far less common, although it seems to be an important factor leading to the rapid discontinuation of LCIG treatment. In this systematic review, we present data on demyelinating polyneuropathy with acute/subacute onset; we identified nine papers including prospective assessments and case reports, with detailed information on 15 patients. In all patients, despite treatment with corticosteroids, intravenous immunoglobulins (IVIG) or plasma exchange (PE), the LCIG therapy was terminated. We also present a case of subacute demyelinating polyneuropathy with effective treatment and continuation of LCIG therapy.

Comparability of Foslevodopa/Foscarbidopa Pharmacokinetics in Healthy Asian and White Participants.

This phase 1 study assessed the safety, tolerability, and pharmacokinetics of a single 24-hour continuous subcutaneous dose of foslevodopa/foscarbidopa in healthy adult Japanese (N = 24), Han Chinese (N = 8), and White (N = 24) participants. Three doses of foslevodopa/foscarbidopa were evaluated in healthy participants for this study: 480/24, 960/48, and 1440/72 mg/day. Serial blood samples for measurement of levodopa, carbidopa, foslevodopa, foscarbidopa, and 3-O-methyldopa concentrations were collected for 48 hours after foslevodopa/foscarbidopa administration. Safety and tolerability were assessed throughout the study. Point estimates for ratios of central values indicated that the exposure difference between Japanese and White participants was <10%. The maximum concentration and area under the plasma concentration-time curve for both LD and CD following foslevodopa/foscarbidopa continuous subcutaneous infusion were comparable between Han Chinese and White participants. Point estimates for ratios of central values indicated that the exposure difference between Han Chinese and White participants was <14%. The regimens tested were generally well tolerated, and no new safety issues were identified in this study. There were no clinically meaningful differences in LD and CD exposures or pharmacokinetics following administration of foslevodopa/foscarbidopa among White, Japanese, and Han Chinese participants.

Determination of the motor status of patients with advanced Parkinson's disease under levodopa-carbidopa intestinal gel using a machine learning model.

BACKGROUND: Despite the careful selection of candidate patients, the levodopa-carbidopa intestinal gel (LCIG) treatment of advanced Parkinson's disease (PD) remains challenging due to a complex interplay between motor and non-motor symptoms. We developed a random forest (RF) model to determine the postoperative motor outcome of patients with advanced PD at 2 years under the LCIG therapy by using motor and non-motor data from a Greek multicenter, observational registry (ForHealth S.A.). METHODS: This was a prospective 24-month, observational study of 59 patients with advanced PD under LCIG treatment from September 2019 to September 2021. Motor status was assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) parts III and IV. Non-motor symptoms (NMS) were assessed by the Non-Motor Symptoms Questionnaire (NMSQ) and the Geriatric Depression Scale (GDS). RESULTS: We demonstrated that the proper combination of motor and non-motor measures significantly determines the motor outcome (UPDRS-III year 2: 23.57 ± 14.22 p < 0.001), reducing the RMSE (root-mean-square-error) from 3.487279 to 3.066292, suggesting that the optimized model performed well. Based on the "IncNodePurity," the major determinant factors of UPDRS-III (year 2) were, in descending order: UPDRS-III (year 0), disease duration, NMSQ (year 2), age, NMSQ (year 0), time off (hours) (year 2), time dyskinesia (year 0), quality of life (year 2) after the LCIG implementation. CONCLUSIONS: The novelty of this model is the possibility to determine the motor outcome after two years of LCIG. This model could be also useful for not specialized Parkinson's neurologists, to improve patient counseling, expectation management, and patient satisfaction with LCIG therapy.

Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson's disease: a randomised, double-blind, active-controlled, phase 3 trial.

BACKGROUND: Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease. METHODS: A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142. FINDINGS: Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (-2·75 [0·50] vs -0·96 [0·49] h; difference -1·79 h, -3·03 to -0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild-moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group. INTERPRETATION: Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease. FUNDING: AbbVie.

The safety and tolerability of levodopa eye drops for the treatment of ocular disorders: A randomized first-in-human study.

Myopia is the leading cause of low vision worldwide and can lead to significant pathological complications. Therefore, to improve patient outcomes, the field continues to develop novel interventions for this visual disorder. Accordingly, this first-in-human study reports on the safety profile of a novel dopamine-based ophthalmic treatment for myopia, levodopa/carbidopa eye drops. This phase I, first-in-human, monocenter, placebo-controlled, double-blind, paired-eye, multidose, randomized clinical trial was undertaken in healthy adult males aged 18-30 years (mean age 24.9 ± 2.7) at the University of Canberra Eye Clinic, Australia. Participants were randomly assigned to receive either a low (1.4 levodopa:0.34 carbidopa [µmoles/day], n = 14) or standard dose (2.7 levodopa:0.68 carbidopa [µmoles/day], n = 15) of levodopa/carbidopa eye drops in one eye and placebo in the fellow eye once daily for 4 weeks (28 days). Over this 4-week trial, and after a 4-month follow-up visit, levodopa/carbidopa treatment had no significant effect on ocular tolerability and anterior surface integrity, visual function, ocular health, refraction/ocular biometry, and did not induce any non-ocular adverse events. These results indicate that topical levodopa/carbidopa is safe and tolerable to the eye, paving the way for future studies on the efficacy of this novel ophthalmic formulation in the treatment of human myopia. The findings of this study have implications not only for the treatment of myopia, but in a number of other visual disorders (i.e., amblyopia, diabetic retinopathy, and age-related macular degeneration) in which levodopa has been identified as a potential clinical intervention.

Adverse effects of levodopa/carbidopa intrajejunal gel treatment: A single-center long-term follow-up study.

OBJECTIVES: Levodopa/carbidopa intrajejunal gel (LCIG) is an effective therapeutic strategy to overcome levodopa-induced motor complications in advanced Parkinson's disease (PD). However, it requires invasive percutaneous endoscopic gastrojejunostomy (PEG-J) and may be associated with serious adverse effects (AE). In this study, we aimed to evaluate long-term AEs related to LCIG treatment in a large homogenous cohort of advanced PD patients. METHODS: One hundred three consecutive PD patients were regularly monitored for LCIG-related, PEG-J-related, and device-related AEs up to 14 years. Incidence of AEs was studied in time applying a time-to-event analysis and Cox proportional hazard model with age, disease duration, gender, and recurrent AE as covariates. Health-related quality of life (HRQoL) was estimated at each visit and compared to HRQoL before the LCIG treatment. RESULTS: Among 296 AEs noted, 48.8% were LCIG-related, 32.4% PEG-J-related, and 19.6% device-related. While most of the studied AEs steadily accumulated throughout the follow-up period, 24.3% of the patients (95% CI 10.1%-36.3%) experienced PEG-J-related AE already within the first days after the PEG-J insertion. Cox model revealed that older patients had higher probability of psychosis, PEG-J- and device-related AEs (p < .05, p < .05, and p = .02) and suggested increased recurrence risk in those with early PEG-J and device-related AEs. Despite relatively high incidence of AEs, HRQoL significantly increased in the follow-up period (p < .0001). CONCLUSION: AEs related to LCIG treatment are common. Therefore, careful patient selection and monitoring throughout the treatment is recommended, especially in those with early side effects. Nevertheless, LCIG significantly improves HRQoL in advanced PD patients on a long term.

Practical pearls to improve the efficacy and tolerability of levodopa in Parkinson's disease.

INTRODUCTION: Levodopa is the most effective medication for the treatment of motor symptoms of Parkinson's disease (PD). Several factors may affect the efficacy and tolerability of levodopa. These include the timing, dosage and administration of levodopa, concomitant drugs, food, PD-associated non-motor symptoms, and various neurologic and non-neurologic comorbidities. If not appropriately addressed, these issues may limit levodopa efficacy, tolerability, and compliance. AREAS COVERED: This article reviews the basics of the metabolism of orally administered levodopa, its side effects, and the factors that may affect its tolerability and efficacy. We provide several practical pearls to improve the tolerability and efficacy of levodopa. EXPERT OPINION: Protein-rich food delays and reduces levodopa absorption. Hence, levodopa should preferably be administered in a relatively empty stomach. Carbidopa dosing is crucial as it not only enhances the entry of levodopa into the central nervous system but also reduces levodopa's peripheral adverse effects. Patients experiencing the early side effects such as nausea/vomiting should be prescribed with anti-nausea medications that do not block dopamine receptors. Non-oral routes of administration can be used to obviate persistent gastrointestinal side effects. Implementation of these and other tips may help improve the tolerability and efficacy of levodopa.

Determination of levodopa by chromatography-based methods in biological samples: a review.

Levodopa (L-DOPA) is the most effective drug for Parkinson's disease; however, various side effects occur during therapy. L-DOPA metabolites and the high cumulative dose of L-DOPA were responsible for its side effects. It is necessary to monitor the concentration of L-DOPA and its metabolites for individualized therapy. This review focuses on L-DOPA analysis by chromatography-based methods in biological matrices. Literature published up to September 2021 was collected in the PubMed, Web of Science, and Embase by using search strategy ("levodopa" OR "L-DOPA") AND ("chromatography"). A total of 1249 articles were identified and 32 articles were included. The contents for method development and validation were summarized and analyzed. Due to the instability of catecholamines (L-DOPA, dopamine, and 3-O-methyldopa) and carbidopa, antioxidation (0.5 mg sodium metabisulfite for 100 µL sample) and environment temperature control were used alone or in combination to enhance stability. Sample was mainly pretreated by protein precipitation (0.4-0.7 M perchloric acid). Separation was usually achieved using methanol or acetonitrile:water (with formic acid) on C18 columns. Mass spectrometry, electrochemical detector, ultraviolet-visible detector and fluorescence detector were used for detection. For L-DOPA, the calibration range was 2.5-10,000 ng/mL, the matrix effect and its coefficient of variation was 85-115 and -9.0-8.5%, and the recovery was 66.8-127.0%. Without stabilization strategy, L-DOPA was stable in plasma at room temperature for 1-7 h (4-6 h for most studies), at - 70 °C to - 80 °C for 10-20 days and after 3-5 freeze-thaw cycles. With stabilization strategies, the stability of L-DOPA in plasma was significantly improved. Metabolites of L-DOPA and enzyme inhibitors (carbidopa, entacapone, tolcapone and benserazide) were all stable in biological matrix. This study might be useful for researchers to develop their methods for individualized therapy of patients with Parkinson.