Efficacy and Safety of Entacapone Combined With Madopar in the Treatment of Early Parkinson's Disease (PD): A Prospective, Multicenter, Non-Randomized Controlled Study

This study aims to evaluate the efficacy and safety of combining entacapone with Madopar (levodopa/benserazide) in the treatment of early-stage Parkinson's disease (PD). Levodopa is the most effective medication for PD, but long-term use often causes motor complications due to its short half-life. Entacapone is a COMT inhibitor that can prolong levodopa's effect and stabilize its blood levels.

This prospective, multicenter, non-randomized controlled study will recruit early PD patients and assign them to either a Madopar-only group or a Madopar plus entacapone group. Participants will be treated for 24 weeks. The primary outcome is the change in motor symptoms measured by the MDS-UPDRS Part III score from baseline to week 24. Secondary outcomes include changes in daily living ability, quality of life, cognitive function, and safety indicators.

The study is designed to provide evidence on whether early combination therapy can offer better outcomes compared to Madopar alone.

Parkinson's disease (PD) is a common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic neurons in the central nervous system. Levodopa, the precursor of dopamine, is widely recognized as the most effective treatment for alleviating motor symptoms such as tremor, rigidity, and bradykinesia. However, due to its short half-life and rapid peripheral metabolism, levodopa monotherapy often results in low bioavailability and long-term motor complications such as wearing-off and dyskinesia.

To enhance its efficacy and tolerability, levodopa is typically combined with a peripheral decarboxylase inhibitor, benserazide, forming the compound medication Madopar (levodopa/benserazide, referred to as LB). LB is commonly used as a first-line therapy in early-stage PD patients, particularly in clinical practice across China.

Recent evidence suggests that further adding entacapone-a catechol-O-methyltransferase (COMT) inhibitor-can extend levodopa's half-life, stabilize plasma concentrations, and reduce motor fluctuations. This triple combination of levodopa, benserazide, and entacapone (referred to as LBE) has shown clinical benefits in patients with advanced PD who experience wearing-off phenomena. LBE may reduce the risk of dyskinesia and improve symptom control by maintaining steadier dopamine levels.

However, the potential role of LBE in the early stage of PD remains unclear, especially in the Chinese population, where high-quality, prospective evidence is limited. This study is designed to evaluate the efficacy and safety of LBE compared to LB in early-stage PD through a prospective, multicenter, non-randomized controlled trial.

Eligible patients will be divided into two cohorts based on their prior levodopa use (naïve or stable use ≥1 month) and assigned in a 1:1 ratio to either the LB or LBE group. The intervention period is 24 weeks. Clinical outcomes will be assessed using the MDS-UPDRS scores, quality of life measures, cognitive scales, and safety evaluations.

The results of this study will help determine whether early combination therapy with entacapone offers clinical advantages over Madopar monotherapy and provide evidence to support treatment optimization strategies for early-stage Parkinson's disease in Chinese patients.

Eligibility Criteria:
Inclusion Criteria:

Age between 18 and 80 years;

Diagnosed with Parkinson's Disease based on the MDS criteria, confirmed by a movement disorder neurologist;

Modified Hoehn and Yahr stage between 1 and 2.5;

No prior use of entacapone;

MMSE score ≥ 26;

BDI (Beck Depression Inventory) score \< 15;

Either:

Has never used levodopa before, or

Has been on a stable dose of levodopa (300-600 mg/day) for at least 1 month prior to enrollment;

Stable doses of amantadine, anticholinergics, dopamine agonists, selegiline, or rasagiline are allowed if maintained for at least 30 days prior to and during the study;

Willing and able to give informed consent and comply with study procedures, with caregiver support if needed.

Exclusion Criteria:

Previous use of entacapone or tolcapone for more than 30 days, or within 4 weeks before baseline;

Use of dopamine agonists within 4 weeks before baseline;

BDI score ≥ 15;

MMSE score \< 26;

Unstable levodopa dosage;

History of dyskinesia;

Diagnosis of atypical or secondary parkinsonism, or history of PD-related neurosurgery;

Clinically significant medical conditions within the past 5 years that could interfere with study participation;

Use of medications known to induce parkinsonism;

Participation in other investigational drug trials within 30 days before baseline.