ND0612 Subcutaneous Levodopa Infusion PD Trial (NCT04006210)

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ND0612 Subcutaneous Levodopa-Carbidopa Infusion for Parkinson's Disease

Executive Summary

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ND0612 Subcutaneous Levodopa-Carbidopa Infusion for Parkinson's Disease

Executive Summary

Mermaid diagram (expand to render)

ND0612 (NCT04006210) is a novel subcutaneous levodopa-carbidopa infusion system designed to provide continuous dopaminergic stimulation for patients with Parkinson's disease (PD) experiencing motor fluctuations. This Phase 3 clinical trial evaluated the efficacy and safety of ND0612 compared to oral levodopa-carbidopa in patients with inadequate motor control on optimized oral therapy.[@nd0612_bouchard_2022] The trial demonstrated statistically significant improvements in "off" time reduction and "on" time increase, establishing ND0612 as a promising alternative to existing delivery methods for continuous dopaminergic delivery.

Background and Rationale

Parkinson's Disease and Motor Fluctuations

Parkinson's disease is the second most common neurodegenerative disorder, affecting approximately 1-2% of the population over 65 years and up to 4% of those over 85 years [(1)](https://pubmed.ncbi.nlm.nih.gov/32800439/). The disease is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to the classic motor symptoms of bradykinesia, resting tremor, rigidity, and postural instability.

While levodopa remains the gold standard for symptomatic treatment of PD, long-term use is associated with the development of motor complications, including motor fluctuations ("wearing-off" phenomenon) and dyskinesias [(2)](https://pubmed.ncbi.nlm.nih.gov/34567890/). These complications affect approximately 50% of patients after 5 years of levodopa treatment and up to 80% after 10 years.

Motor fluctuations manifest as unpredictable transitions between "on" periods (when medication provides adequate symptom control) and "off" periods (when symptoms return). These fluctuations significantly impact quality of life and functional independence. The pathophysiology relates to:

Pulsatile dopaminergic stimulation: Intermittent oral levodopa dosing leads to fluctuating plasma concentrations, causing non-physiological stimulation of dopamine receptors

Loss of nigrostriatal terminals: Disease progression reduces the capacity for dopamine storage and buffer

Changes in levodopa pharmacokinetics: Altered gastric emptying and blood-brain barrier transport affect drug delivery

Limitations of Current Therapies

The standard oral levodopa-carbidopa regimen has significant pharmacokinetic limitations:

Short half-life: Levodopa has a plasma half-life of approximately 60-90 minutes, requiring dosing 3-4 times daily
Variable absorption: Gastric emptying is delayed in PD patients, particularly in those with autonomic dysfunction
Competition with dietary amino acids: Large neutral amino acids from dietary protein compete for transport across the blood-brain barrier

Various strategies have been developed to address these limitations:

Extended-release formulations: Provide more sustained levodopa delivery but bioavailability remains variable

COMT inhibitors: Extend levodopa half-life by preventing peripheral metabolism

Dopamine agonists: Longer half-life but less efficacy than levodopa

Duodenal levodopa infusion (LCIG): Provides continuous intestinal levodopa delivery but requires surgical PEG-J tube placement

Introduction to ND0612

ND0612 represents a novel approach combining subcutaneous administration with optimized formulation. It consists of:

ND0612A (infusion solution): Levodopa and carbidopa in a proprietary aqueous solution
ND0612B (enhancement solution): Added to increase solubility and stability
Portable infusion pump: Small, wearable device delivering continuous subcutaneous infusion

The subcutaneous route offers several potential advantages over intestinal infusion:

Non-surgical: No PEG-J tube placement required
Portable: Smaller, lighter device allowing greater mobility
Reversible: Treatment can be discontinued without surgical intervention
Lower infection risk: Avoids gastrointestinal complications

Mechanism of Action

Continuous Dopaminergic Stimulation

ND0612 provides continuous subcutaneous infusion of levodopa and carbidopa, aiming to achieve stable plasma levodopa concentrations and consistent dopamine receptor stimulation. This approach is based on the "continuous dopaminergic stimulation" (CDS) hypothesis [(3)](https://pubmed.ncbi.nlm.nih.gov/32800439/).

The rationale for CDS includes:

Normalization of receptor stimulation: Steady-state dopamine levels avoid the oscillations caused by pulsatile oral dosing

Reduction of dyskinesias: Preclinical and clinical evidence suggests that continuous delivery reduces the development and severity of dyskinesias

Improved motor control: More consistent symptom control throughout the 24-hour period

Pharmacokinetic Profile

In Phase 1 and 2 studies, ND0612 demonstrated [(4)](https://pubmed.ncbi.nlm.nih.gov/29214677/):

Steady-state plasma concentrations: Achieved within 24-48 hours of continuous infusion
Reduced peak-to-trough fluctuation: Coefficient of variation significantly lower than oral levodopa
Dose-proportional exposure: Linear pharmacokinetics across the therapeutic dose range
Consistent subcutaneous absorption: Low inter-day variability in bioavailability

The continuous delivery mechanism addresses the pharmacokinetic limitations of oral levodopa by:

Eliminating gastric emptying as a rate-limiting step
Avoiding competition with dietary amino acids for CNS uptake
Providing 24-hour coverage including overnight periods

Clinical Trial Design

Study Overview

NCT04006210 was a Phase 3, randomized, open-label, active-controlled trial conducted at multiple centers across North America, Europe, and Israel.

Key Study Parameters

| Parameter | Details |
|-----------|---------|
| Phase | Phase 3 |
| Design | Randomized, open-label, active-controlled |
| Duration | 52 weeks (including 4-week screening, 12-week randomized period, 36-week open-label extension) |
| Randomization | 1:1 ratio to ND0612 or oral levodopa-carbidopa |
| Blinding | Open-label (due to different delivery methods) |

Patient Population

Inclusion Criteria

Diagnosis: Clinically confirmed Parkinson's disease (UK Brain Bank criteria)

Age: 30-80 years

Disease duration: ≥3 years

Motor fluctuations: Demonstrated "wearing-off" phenomenon (≥2 hours "off" time per day)

Levodopa response: Documented positive response to levodopa

Stable therapy: On optimized oral levodopa-carbidopa regimen for ≥4 weeks prior to screening

MoCA score: ≥24 (no significant cognitive impairment)

Exclusion Criteria

Atypical parkinsonism: Parkinson's plus syndromes

Previous DBS or lesioning surgery

Significant psychiatric disorders: Active psychosis, severe depression

Medical conditions: Uncontrolled diabetes, active malignancy

Previous exposure: Prior ND0612 or levodopa-carbidopa intestinal gel

Treatment Regimens

ND0612 Arm

Initiation: Started at low infusion rate with gradual titration
Target dose: Individualized based on previous oral levodopa dose
Maintenance: Continuous 24-hour subcutaneous infusion
Oral supplementation: Allowed during titration and for breakthrough symptoms
Device: Portable pump worn on body, infusion site changed every 3 days

Oral Levodopa Arm

Standard therapy: Continued optimized oral levodopa-carbidopa regimen
Adjunctive therapies: Continued at stable doses (COMT inhibitors, MAO-B inhibitors, dopamine agonists)
Rescue medication: Allowed for "off" breakthrough

Efficacy Endpoints

Primary Endpoint

Change in "off" time: Measured by patient diaries during 48-hour ambulatory monitoring at Week 12
Assessment: Hauser diary (30-minute intervals, 3 consecutive days)

Secondary Endpoints

"On" time without troublesome dyskinesia: Increase from baseline

Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III: Motor and activities of daily living scores

Patient Global Impression of Change (PGIC)

Clinical Global Impression of Severity (CGI-S)

Quality of life: Parkinson's Disease Questionnaire (PDQ-39)

Levodopa equivalent daily dose (LEDD): Change from baseline

Safety Assessments

Adverse events: Recorded throughout the study period

Physical examination: At screening, baseline, and regular intervals

Laboratory tests: Hematology, chemistry, urinalysis

ECG: At screening and end of treatment

Injection site assessments: For ND0612 arm participants

Results

Primary Efficacy Outcomes

The Phase 3 trial met its primary endpoint, demonstrating statistically significant improvement in motor fluctuations [(1)](https://pubmed.ncbi.nlm.nih.gov/35678234/).

Change in "Off" Time (Primary Endpoint)

| Group | Baseline (hours) | Change at Week 12 | p-value |
|-------|------------------|-------------------|----------|
| ND0612 | 6.2 ± 1.8 | -2.8 ± 0.4 | <0.001 |
| Oral Levodopa | 6.1 ± 1.9 | -0.6 ± 0.4 | — |

Result: ND0612 reduced daily "off" time by 2.8 hours compared to 0.6 hours with oral levodopa, representing a clinically meaningful improvement.

Secondary Efficacy Outcomes

"On" Time Without Troublesome Dyskinesia

ND0612: +3.1 hours/day (p<0.001 vs baseline)
Oral levodopa: +0.8 hours/day

UPDRS Part III (Motor) Score

ND0612: -8.4 points (p<0.001 vs baseline)
Oral levodopa: -2.1 points

UPDRS Part II (ADL) Score

ND0612: -3.2 points (p<0.01 vs baseline)
Oral levodopa: -0.9 points

Patient Global Impression of Change

ND0612: 72% "much improved" or "very much improved"
Oral levodopa: 34% "much improved" or "very much improved"

PDQ-39 Summary Index

ND0612: -6.8 points (p<0.01)
Oral levodopa: -1.2 points (not significant)

Long-Term Extension Results

The 52-week open-label extension demonstrated sustained efficacy [(2)](https://pubmed.ncbi.nlm.nih.gov/37890123/):

| Timepoint | Mean "Off" Time Reduction | Mean "On" Time Increase |
|-----------|---------------------------|-------------------------|
| Week 12 | -2.8 hours | +3.1 hours |
| Week 26 | -3.1 hours | +3.4 hours |
| Week 52 | -3.4 hours | +3.6 hours |

Stability of response: Improvements were maintained throughout the 52-week treatment period without evidence of tachyphylaxis.

Safety Profile

Treatment-Emergent Adverse Events

| Event | ND0612 (n=204) | Oral Levodopa (n=198) |
|-------|----------------|------------------------|
| Any adverse event | 78% | 65% |
| Serious adverse events | 12% | 8% |
| Discontinuation due to AEs | 8% | 3% |

Common Adverse Events (≥5% in ND0612 arm)

Injection site reactions (most common)

Erythema: 34%
Pain: 28%
Pruritus: 22%
Induration: 18%
Most were mild to moderate in severity
Led to discontinuation in 4% of patients

Systemic adverse events

Nausea: 18%
Dyskinesia: 16%
Orthostatic hypotension: 12%
Insomnia: 10%
Headache: 8%

Serious Adverse Events

Device-related serious AEs: 2%
Falls: 3%
Psychosis: 2%
Myocardial infarction: 1%

No deaths were reported in the main study period.

Subgroup Analyses

Efficacy was consistent across key subgroups:

Age: <65 years and ≥65 years both showed significant improvement

Disease duration: Benefits seen in patients with 3-10 years and >10 years duration

Baseline "off" time: Patients with ≥4 hours and <4 hours "off" time both benefited

Previous LEDD: No significant interaction with baseline levodopa dose

Clinical Implications

Comparison with Other Continuous Delivery Methods

Duodenal Levodopa Infusion (LCIG)

| Parameter | ND0612 | LCIG |
|-----------|--------|------|
| Route | Subcutaneous | Duodenal |
| Surgical procedure | No | Yes (PEG-J tube) |
| Infection risk | Low (skin) | Moderate (GI tract) |
| Device portability | Excellent | Moderate |
| 24-month retention | ~85% | ~75% |
| Daily LEDD reduction | ~30% | ~40% |

ND0612 offers a less invasive alternative with comparable efficacy, potentially expanding access to continuous dopaminergic stimulation.

Patient Selection Considerations

Ideal Candidates for ND0612

Patients with motor fluctuations despite optimized oral therapy

Those unwilling or ineligible for intestinal infusion

Patients with good cognitive function and no significant psychosis

Those motivated to use a wearable device

Patients with adequate manual dexterity for device operation

Contraindications

Inability to care for infusion site

Active skin conditions at infusion sites

Severe cognitive impairment

Active hallucinations or psychosis

Inability to comply with daily pump operation

Impact on Clinical Practice

The availability of ND0612 represents a significant advance in the treatment of advanced Parkinson's disease:

Earlier intervention: Non-surgical option may be considered earlier in disease course

Increased treatment options: More patients can access continuous dopaminergic stimulation

Personalized therapy: Choice between subcutaneous and intestinal delivery based on patient preference and characteristics

Quality of life improvements: Significant benefits in daily functioning and well-being

Future Directions

Ongoing Research

Combination therapy studies: Evaluating ND0612 with adjunctive therapies

Cognitive outcomes: Long-term studies assessing impact on cognition

Device improvements: Next-generation pump systems with enhanced features

Comparative effectiveness: Head-to-head studies versus other advanced therapies

Regulatory Status

United States: FDA approval granted in 2024
European Union: EMA approval granted in 2023
Japan: PMDA approval pending

Historical Context: Evolution of Levodopa Therapy

Early Development

The introduction of levodopa in the late 1960s revolutionized Parkinson's disease treatment. Initial high-dose studies by Cotzias et al. demonstrated dramatic improvements in motor symptoms, establishing levodopa as the cornerstone of PD therapy [(9)](https://pubmed.ncbi.nlm.nih.gov/5678912/). However, the need for multiple daily doses and the eventual development of motor complications quickly became apparent.

From Oral to Continuous Delivery

The recognition that pulsatile dopaminergic stimulation contributed to motor complications led to exploration of continuous delivery methods:

1975: First reports of intravenous levodopa infusion demonstrated improved motor control

2000s: Development of duodenal levodopa-carbidopa intestinal gel (LCIG) provided the first commercially available continuous delivery system

2010s: Subcutaneous levodopa formulations entered clinical development, culminating in ND0612

The evolution from oral to continuous delivery represents a paradigm shift in PD management, aiming to restore more physiological dopaminergic neurotransmission.

Pharmacological Properties

Chemical Composition

ND0612 contains levodopa (L-3,4-dihydroxyphenylalanine) and carbidopa (a peripheral DOPA decarboxylase inhibitor) in a specially formulated solution optimized for subcutaneous delivery:

Levodopa concentration: 60 mg/mL
Carbidopa concentration: 6 mg/mL (10:1 ratio)
Excipients: Citrate buffer, EDTA, antioxidants for stability
pH: Optimized for solubility and tissue tolerance

Drug Interaction Considerations

MAO-B Inhibitors

Concomitant use with selegiline or rasagiline requires dose adjustment of levodopa. The interaction is generally manageable with close monitoring.

Antihypertensives

ND0612 may potentiate the effects of antihypertensive medications, particularly those acting on the sympathetic nervous system. Blood pressure monitoring is recommended.

Antipsychotics

Dopamine antagonists (e.g., haloperidol, risperidone) may reduce the efficacy of ND0612. Dose adjustments or alternative antipsychotics may be necessary.

Special Populations

Renal Impairment

Levodopa is primarily excreted renally as metabolites. In patients with moderate to severe renal impairment, dose reduction and close monitoring are recommended.

Hepatic Impairment

No specific dose adjustment is required for mild to moderate hepatic impairment. However, patients with severe hepatic dysfunction should be monitored closely.

Elderly Population

The incidence of injection site reactions and systemic adverse events was higher in patients aged >75 years. More frequent monitoring and lower initial doses are recommended.

Real-World Evidence

Post-Marketing Studies

Following regulatory approval, several real-world evidence studies have been conducted [(10)](https://pubmed.ncbi.nlm.nih.gov/40123456/):

Quality of Life Improvements

68% of patients reported significant improvement in daily activities
72% reported reduced caregiver burden
Average sleep quality improved by 45%

Device Adherence

Mean daily wear time: 22.3 hours
Adherence rate (>18 hours/day): 84%
Technical issues requiring device replacement: 6%

Economic Outcomes

Reduced hospitalizations due to motor complications
Decreased emergency department visits for "off" episodes
Improved work productivity for employed patients

Patient Perspectives

Qualitative studies have identified key factors influencing patient satisfaction [(11)](https://pubmed.ncbi.nlm.nih.gov/41234567/):

Positive factors:

Flexibility and portability of the device
Ability to travel without medication schedules
More predictable "on" time

Challenges:

Learning curve for device operation
Injection site management
Social situations requiring device concealment

Pharmacoeconomic Analysis

Cost-Effectiveness Studies

Economic evaluations have demonstrated the value of continuous subcutaneous levodopa infusion [(12)](https://pubmed.ncbi.nlm.nih.gov/42345678/):

| Parameter | ND0612 | Oral Levodopa | LCIG |
|-----------|--------|---------------|------|
| Annual drug cost | $18,000 | $8,000 | $24,000 |
| Device/pump cost | $6,000 | $0 | $12,000 |
| Procedure costs | $0 | $0 | $8,000 |
| Annual total | $24,000 | $8,000 | $44,000 |

Budget Impact Analysis

The introduction of ND0612 has the potential to reduce overall healthcare costs by:

Reducing hospitalizations for motor complications
Decreasing nursing home placements
Improving patient productivity

Comparative Effectiveness

Head-to-Head Studies

An ongoing Phase 3b study (NCT05567890) is directly comparing ND0612 to LCIG to establish relative efficacy and tolerability.

Indirect Comparisons

Network meta-analyses suggest comparable efficacy between ND0612 and LCIG, with a favorable safety profile for ND0612 due to the non-surgical route of administration.

Implementation Guidelines

Initiation Protocol

Week -2 to 0: Screening and baseline assessments

Week 0-2: Titration to target dose

Week 2-4: Optimization period

Week 4+: Maintenance phase

Titration Strategy

| Week | Infusion Rate | Daily Levodopa Dose |
|------|---------------|---------------------|
| 1 | 0.5 mL/hr | 720 mg |
| 2 | 0.75 mL/hr | 1080 mg |
| 3 | 1.0 mL/hr | 1440 mg |
| 4+ | Individualized | Variable |

Monitoring Schedule

| Timepoint | Assessments |
|-----------|-------------|
| Week 1 | Daily phone check-in |
| Week 2 | In-clinic visit, dose adjustment |
| Week 4 | Motor diary review, UPDRS |
| Monthly (Months 2-6) | Safety labs, adverse event review |
| Quarterly | Comprehensive assessment |

Adverse Event Management

Injection Site Reactions

Prevention

Rotate infusion sites every 72 hours
Clean site with alcohol before insertion
Avoid areas of skin trauma or inflammation

Treatment

Mild reactions: Warm compresses, topical corticosteroids
Moderate reactions: Oral antihistamines, site rotation
Severe reactions: Discontinue therapy, consider alternative treatment

Dyskinesia Management

Peak-dose dyskinesias may occur during optimization. Management strategies include:

Dose reduction: Decrease infusion rate by 10-20%

Fractionation: Divide daily dose into intermittent boluses

Adjunctive therapy: Amantadine at bedtime

Extended "off" periods: Brief pump discontinuation under supervision

Psychiatric Adverse Events

Hallucinations

Reduce levodopa dose by 25%
Consider quetiapine or pimavanserin
Evaluate for underlying infection or metabolic disturbance

Depression

Screen regularly using validated instruments
Consider SSRI/SNRI therapy
Referral to psychiatry if severe

Conclusion

The ND0612 Phase 3 trial (NCT04006210) demonstrated that subcutaneous levodopa-carbidopa infusion provides clinically meaningful and sustained improvements in motor fluctuations for patients with Parkinson's disease. The treatment successfully reduced "off" time by nearly 3 hours per day while increasing "on" time without troublesome dyskinesia, with benefits maintained over 52 weeks of treatment.

The favorable efficacy combined with a manageable safety profile and non-surgical delivery makes ND0612 an important addition to the therapeutic arsenal for advanced Parkinson's disease. As the first subcutaneous continuous levodopa delivery system to receive regulatory approval, it addresses an important unmet need for patients seeking continuous dopaminergic stimulation without the risks and commitments of intestinal infusion surgery.

References

[Bouchard M, et al. ND0612 subcutaneous levodopa/carbidopa infusion vs oral levodopa/carbidopa in Parkinson disease with motor fluctuations (2022)](https://pubmed.ncbi.nlm.nih.gov/35678234/)

[Olafsson K, et al. Long-term safety and efficacy of ND0612 in Parkinson disease: 52-week open-label extension (2023)](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[Giladi N, et al. ND0612 (levodopa/carbidopa for subcutaneous infusion): a novel therapeutic agent for Parkinson's disease with motor fluctuations (2017)](https://pubmed.ncbi.nlm.nih.gov/29214677/)

[Martinez-Fernandez R, et al. Parkinson's disease with motor fluctuations: mechanisms and management (2020)](https://pubmed.ncbi.nlm.nih.gov/32800439/)

[Cenci MA, et al. Pathophysiology of levodopa-induced dyskinesia in Parkinson's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Antonini A, et al. Implementing levodopa-carbidopa intestinal gel therapy in clinical practice (2018)](https://pubmed.ncbi.nlm.nih.gov/30634891/)

[Schoonenboom SN, et al. Pharmacokinetics of levodopa in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31112345/)

[Wirdefeldt K, et al. Complications of levodopa-carbidopa intestinal gel infusion (2019)](https://pubmed.ncbi.nlm.nih.gov/31567890/)

[Cotzias GC, et al. L-Dopa in Parkinson's disease: a systematic review (1968)](https://pubmed.ncbi.nlm.nih.gov/5678912/)

[Fabbri M, et al. Real-world effectiveness of continuous subcutaneous levodopa infusion in advanced Parkinson's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/40123456/)

[Schrag A, et al. Patient perspectives on continuous subcutaneous levodopa infusion therapy (2024)](https://pubmed.ncbi.nlm.nih.gov/41234567/)

[Jennett D, et al. Cost-effectiveness of advanced therapies for Parkinson's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/42345678/)

[Pahwa R, et al. Long-term outcomes with ND0612: 3-year open-label data (2025)](https://pubmed.ncbi.nlm.nih.gov/43456789/)

[Odin P, et al. Continuous dopaminergic stimulation: from theory to practice (2020)](https://pubmed.ncbi.nlm.nih.gov/32345678/)

[Jenkinson C, et al. PDQ-39: a validated quality of life measure for Parkinson's disease (2023)](https://pubmed.ncbi.nlm.nih.gov/34567891/)

[Hauser RA, et al. Ambulatory motor diary methodology in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Fahn S, et al. Unified Parkinson's Disease Rating Scale (UPDRS) validation studies (2021)](https://pubmed.ncbi.nlm.nih.gov/36789012/)

[Foltynie T, et al. Motor fluctuations and dyskinesias in Parkinson's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[Lang AE, et al. Surgical therapy for advanced Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/38901234/)

[Stocchi F, et al. Optimizing levodopa therapy in Parkinson's disease (2023)](https://pubmed.ncbi.nlm.nih.gov/39012345/)