Lessons Learned From a Delayed-Start Trial of Modafinil for Freezing of Gait in Parkinson’s Disease
Commentary by Prof. Stewart Factor
This is a 24-week, single site, randomized, double-blind, placebo-controlled, delayed start trial of modafinil 50 mg in the treatment of PD patients with freezing of gait (FOG). Half the patients are treated with early start modafinil for 24 weeks and the other half 12 weeks of placebo followed by 12 weeks of modafinil. Primary outcome measures are change in FOG-Q and in gait stride length during continuous gait as measured on a gait mat at 12 weeks. There are several secondary and exploratory measures and video annotation of FOG to examine % time frozen (%TF). Twenty-one patients were enrolled and the results were ostensibly negative with no significant changes in any outcome measures. However, changes trended in the right directions. One example was improvement in %TF in 8 of 11 subjects after 12 weeks of treatment (4%), and subsequent worsening after 2 weeks washout. They conclude that larger studies may be indicated.
There are two interesting topics of discussion. The authors discussed the difficulties in performing treatment trials on FOG. FOG is unpredictable and may not occur in the lab or clinic. In this study only 11 of 21 froze at baseline. The subjective measure FOG-Q is not an effective outcome measure. Video annotation, while being developed through ICFOG and the current gold standard, is an arduous and time-consuming task and impractical for large trials and the use of in-home video monitoring. It requires automated machine learning programs to make it practical. Further, in-laboratory tasks that instigate FOG are not necessarily translatable to home life. Finally, the clinically meaningful change in various measures is still to be determined.
Second is the use of the atypical stimulant modafinil and its ability to promote gamma activity in the PPN, which is hypothesized to improve gait in PD, but yet to be proven. The impact of increased gamma activity is interesting. In STN and cortex in PD undergoing DBS are often associated with improved function and dyskinesia. Gamma activity can also impact several proteomic changes in the brain that might be relevant to FOG including the clearance of amyloid. Modafinil also boosts noradrenergic activity which has been associated with improved FOG as well.
I agree with the authors, further work is needed.
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