Research Paper

Pharmaceutical Research

, Volume 24, Issue 4, pp 791-802

First online:

Levodopa Slows Progression of Parkinson’s Disease. External Validation by Clinical Trial Simulation

  • Phylinda L. S. ChanAffiliated withDepartment of Pharmacology and Clinical Pharmacology, University of Auckland
  • , John G. NuttAffiliated withDepartment of Neurology and Physiology & Pharmacology, Portland VA Medical Center and Oregon Health Sciences University
  • , Nicholas H. G. HolfordAffiliated withDepartment of Pharmacology and Clinical Pharmacology, University of AucklandDepartment of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland Email author 

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To externally validate the model predictions of a DATATOP cohort analysis through application of clinical trial simulation with the study design of the ELLDOPA trial.


The stochastic pharmacokinetic-pharmacodynamic and disease progress model was developed from the large DATATOP cohort of patients followed for 8 years. ELLDOPA was designed to detect a difference between placebo and levodopa treated arms in the total Unified Parkinson’s Disease Rating Scale (UPDRS) taken at baseline and following 2 weeks levodopa washout after 40 weeks of treatment. The total UPDRS response was simulated with different assumptions on levodopa effect (symptomatic with/without disease modifying capability) and washout speed of symptomatic effect.


The observed results of ELLDOPA were similar to the model predictions assuming levodopa slows disease progression and has a slow washout of symptomatic effect.


This simulation work confirmed the conclusion of the DATATOP analysis finding that levodopa slows disease progression. The simulation results also showed that a dose-related increased rate of progression in Parkinson’s disease, obscured by symptomatic benefit, is very unlikely. Finally, the simulation results also shown that 2 weeks washout period was not adequate to completely eliminate the symptomatic benefits of levodopa.

Key words

clinical trial simulation DATATOP disease progress model ELLDOPA Parkinson’s disease protective treatment