Lessons Learned From a Delayed-Start Trial of Modafinil for Freezing of Gait in Parkinson's Disease

Freezing of gait (FOG) in people with Parkinson's disease (PwPD) is debilitating and has limited treatments. Modafinil modulates beta/gamma band activity in the pedunculopontine nucleus (PPN), like PPN deep brain stimulation. We therefore tested the hypothesis that Modafinil would improve FOG in PwPD.

PwPD with FOG were randomized to early-start (24 weeks modafinil) or delayed-start (12 weeks each, placebo then modafinil) of oral modafinil 50 mg, followed by a 2-week washout for both arms. Primary outcomes were change in OFF-levodopa stride length and FOG questionnaire scores; secondary outcomes were change in motor Unified Parkinson's Disease Rating Scale (UPDRS), sleep and quality-of-life scores, and post hoc outcome was change in percent freezing time (%FT).

Early- (n = 12) and delayed-start (n = 9) group participants were well matched for age, OFF-levodopa motor UPDRS and FOG-Q scores. Primary and secondary outcomes did not reach statistical significance. Limiting the analysis to study completers with quantifiable visualized freezing at the initial visit and collapsing the two study arms (n = 11), %FT trended to improvement with 50 mg modafinil in 8/11 participants (p = 0.15) and worsening after 2 weeks washout in 9/11 participants (p = 0.09). A future cross-over study with 50 participants would have 0.80 power to detect a 0.5 standard-deviation improvement in %FT.

For future therapeutic trials, selecting PwPD with moderate, quantifiable FOG and utilizing appropriate outcome measures like %FT will improve the ability to identify intervention effects. Even for short trials, analyses must account for gait decline. An FOG outcome measure that requires less analysis time burden than video quantification, and the ability for at-home monitoring is needed.