Levodopa slows progression of Parkinson's disease: external validation by clinical trial simulation.
OBJECTIVE
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.


METHODS
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.


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


CONCLUSIONS
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.
Chan
Phylinda L S
PL
Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
Nutt
John G
JG
Holford
Nicholas H G
NH
D000978:Antiparkinson Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D003198:Computer Simulation; D018450:Disease Progression; D005500:Follow-Up Studies; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008954:Models, Biological; D010300:Parkinson Disease / Q000188:drug therapy*; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome
D000978:Antiparkinson Agents; D007980:Levodopa