PURPOSE: 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.
RCT Entities:
PURPOSE: 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.
Authors: M G Murer; G Dziewczapolski; L B Menalled; M C García; Y Agid; O Gershanik; R Raisman-Vozari Journal: Ann Neurol Date: 1998-05 Impact factor: 10.422
Authors: Paulo Guimaraes; Karl Kieburtz; Christopher G Goetz; Jordan J Elm; Yuko Y Palesch; Peng Huang; Bernard Ravina; Caroline M Tanner; Barbara C Tilley Journal: Clin Trials Date: 2005 Impact factor: 2.486