PREMANDYSK
(2026)Objective
To investigate whether early adjunctive immediate-release amantadine reduces the risk of peak-dose levodopa-induced dyskinesia in early Parkinson's disease patients without motor complications, and whether any such effect reflects a long-lasting mechanism.
Study Summary
• Adjunctive amantadine-IR halved 18-month dyskinesia incidence versus placebo (11% vs 22%, P=0.025; OR 0.43, 95% CI 0.19–0.98)
• Amantadine-IR group required significantly smaller levodopa dose increases over 18 months (70 mg/day less, 95% CI 21–119 mg, P=0.005)
• Long-lasting or disease-modifying effects could not be demonstrated: LID rates were non-significantly lower at end of delayed-start (12% vs 20%, P=0.13) and washout phases (16% vs 22%, P=0.23)
• Exploratory findings showed mild but significant benefits on freezing of gait, fatigue, and quality of life
• Amantadine-IR group required significantly smaller levodopa dose increases over 18 months (70 mg/day less, 95% CI 21–119 mg, P=0.005)
• Long-lasting or disease-modifying effects could not be demonstrated: LID rates were non-significantly lower at end of delayed-start (12% vs 20%, P=0.13) and washout phases (16% vs 22%, P=0.23)
• Exploratory findings showed mild but significant benefits on freezing of gait, fatigue, and quality of life
Intervention
Amantadine immediate-release 200 mg/day (100 mg capsule in the morning + 100 mg capsule at midday) as add-on to stable levodopa therapy for 18 months
Inclusion Criteria
Age ≥35 years; PD diagnosis; levodopa therapy for ≥2 months but <1 year at ≥150 mg/day; free from levodopa-associated motor complications; stable antiparkinsonian medications ≥1 month before randomization
Study Design
Arms: Amantadine-IR 200 mg/day (n=99) vs Placebo (n=108)
Patients per Arm: 99 vs 108
Outcome
• Primary (18 months): LID developed in 11% (amantadine-IR) vs 22% (placebo), P=0.025; OR 0.43 (95% CI 0.19–0.98, P=0.045); Kaplan-Meier log-rank P=0.042
• Levodopa dose increase 70 mg/day lower in amantadine-IR group (P=0.005)
• Period 2 (all on amantadine, delayed-start): 12% vs 20%, P=0.13 (NS); Period 3 (washout): 16% vs 22%, P=0.23 (NS)
• Significant exploratory benefits on freezing of gait, fatigue, and quality of life during Period 1
• Levodopa dose increase 70 mg/day lower in amantadine-IR group (P=0.005)
• Period 2 (all on amantadine, delayed-start): 12% vs 20%, P=0.13 (NS); Period 3 (washout): 16% vs 22%, P=0.23 (NS)
• Significant exploratory benefits on freezing of gait, fatigue, and quality of life during Period 1