By Claire Henchcliffe, MD

Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

Dr. Henchcliffe reports she is on the speakers bureau and advisory boards for Teva, IMPAX, and ACADIA, and receives grant/research support from Biogen and Kaneka.

SYNOPSIS: A randomized, double-blind, placebo-controlled Phase II clinical trial of oral rivastigmine in 130 patients with moderate-stage Parkinson’s disease demonstrated improved gait stability as measured by accelerometry, and suggested an association with lower rate of falls.

SOURCE: Henderson EJ, et al. Rivastigmine for gait stability in patients with Parkinson’s disease (ReSPonD): A randomized, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016 Jan. 12; doi: 10.1016/S1474-4422(15)00389-0. [ePub ahead of print] .

Gait instability and falls become increasingly important as Parkinson’s disease (PD) advances, but these symptoms are very challenging to treat. However, recent evidence has pointed to an associated cholinergic deficit that might be amenable to acetylcholinesterase treatment. Henderson et al undertook a Phase II, randomized, double-blind, placebo-controlled study of oral rivastigmine, up to 12 mg daily over 32 weeks in 130 patients with moderate PD at risk of falls. Participants had a median age of 69 years (range 46-88 years) in the placebo group and 71 years (range 54-90 years) in the rivastigmine group. In the placebo and rivastigmine groups, median disease duration was 9 years (range 5-13 years) and 8 years (range 5-13 years), respectively. Participants in both groups had experienced approximately five falls within the year prior to enrollment. Median MoCA scores were 26 (range 23-27) in the placebo group and 24 (range 22-27) in the rivastigmine group. Participants were administered oral rivastigmine, beginning with 1.5 mg twice daily or equivalent placebo. Every 4 weeks, the dose was increased by 3 mg daily to a target of 12 mg daily, if tolerated, by 16 weeks. This was followed by a 12-week maintenance phase, with subsequent monitoring to the 1-year time point.

Gait variability was assessed by accelerometry to record step time variability in three conditions: 1) normal walking over 22 meters, 2) simple dual task, in which subjects walked while naming words beginning with a single letter, and 3) complex dual task in which subjects walked while naming words beginning with two alternating letters. Subjects in the rivastigmine group performed better in the simple walking task, with 28% lower step time variability (P = 0.002), and in the simple dual task with 21% lower step rate variability (P = 0.045), but not in the complex dual task. Falls per month were also lower in the rivastigmine vs placebo group (1.4 ± 2.47 vs 2.4 ± 4.40, P = 0.002), although one subject with an extremely high number of falls in the rivastigmine arm was excluded from analysis. Freezing of gait, fear of falling, and cognition and mood measures were not significantly different between groups. In the rivastigmine group, two patients died (unrelated to trial drug) and four patients withdrew, compared with one death and no withdrawals in the placebo group. Two serious adverse events, both worsening Parkinsonism, were rated as probably or definitely rivastigmine-related. The most common adverse event in the rivastigmine arm was nausea (31%).

COMMENTARY

Treating gait disorders, imbalance, and falls in the clinic can be challenging, and increasing dopaminergic treatments, such as levodopa, is not always helpful. This has prompted further examination of other pathways contributing to gait instability and falls that might be amenable to treatment. Rivastigmine, a widely used acetylcholinesterase inhibitor, is currently approved for treatment of PD dementia, in which cholinergic deficits in the nucleus basalis of Meynert are recognized. Now, the importance of the cholinergic system in gait stability and imbalance has been increasingly recognized over recent years, making this system, including the pedunculopontine nucleus, a promising therapeutic target. Therefore, it is important that the present study succeeds in demonstrating an effect of rivastigmine on gait. The authors chose this primary outcome measure, measured by accelerometry, as a surrogate marker of fall risk, but the study also found a rivastigmine-associated decrease in the fall rate itself.

Given the importance of this finding, a few caveats need to be mentioned. Although the study was double-blinded, the authors reported that a post-hoc analysis using a standardized blinding index suggested that more participants in the rivastigmine group were able to correctly guess their intervention than by chance. There were some differences between groups; for example women were under-represented in the placebo arm, and the levodopa equivalent dose was greater and cognition was slightly worse in the placebo arm. Nonetheless, this study strongly supports testing in a larger cohort, possibly with the more tolerable transdermal preparation of rivastigmine. With previous benefit demonstrated in smaller studies of donepezil, it looks more likely that use of an acetylcholinesterase inhibitor might in the future join current recommendations for treating gait and balance. In the meantime, we should not neglect non-pharmacologic interventions, including balance therapy or Tai Chi.