Daniel M. Keller, PhD

July 22, 2015

SAN DIEGO — Treatment with rivastigmine (Exelon, Novartis) improves gait variability of patients with Parkinson's disease (PD) without dementia during normal walking and performance of a simple cognitive task, randomized phase 2 results show.

Treatment also reduces the frequency of falls, the results, from the Rivastigmine to Stabilize Gait in Parkinson's Disease (ReSPOnD) trial, show.

"You can see at follow-up, active treatment with rivastigmine reduced...gait variability, ie, improved...walking stability, and that effect was most prominent in normal walking," Emily Henderson, MBChB, clinical research fellow at the University of Bristol in the United Kingdom, told Medscape Medical News.

She reported the findings here at the 19th International Congress of Parkinson's Disease and Movement Disorders (MDS).

Active treatment with rivastigmine reduced...gait variability, ie, improved...walking stability, and that effect was most prominent in normal walking. Dr Emily Henderson

Gait (step time) variability is a proxy marker for fall risk. The higher the gait variability, the more risky and unsteady is one's walking, and the higher the chance of falling.

In addition to normal walking, she said, patients in this study were also asked to walk while performing a simple cognitive task and then a more complex task to assess the influence of cognitive function on walking ability.

Aside from physical injury and hospitalization, the fear of future falls can lead to loss of independence and confidence, so fall risk is a major concern of patients with PD. Compensating for gait dysfunction requires more cognitive attention, but PD-related cognitive impairment can limit patients' cognitive reserve.

In this 8-month, phase 2, double-blind, randomized, placebo-controlled trial performed in a single center in the United Kingdom, researchers tested the effect of the cholinesterase inhibitor rivastigmine on patients with PD who had fallen in the past year. The 130 participants with Hoehn and Yahr stage 2-3 disease had to be able to walk 18 meters without aids, did not have dementia, and could not be receiving a cholinesterase inhibitor at study entry.

The first 4 months of the trial were an up-titration period, and then patients maintained their highest tolerated dose for the next 4 months.

Participants filled out monthly falls diaries and were telephoned monthly. Gait was assessed with an accelerometer on a 22-meter trajectory. At baseline, the groups were well matched for age, cognitive assessment scores, number of falls in the prior year (approximately five), gait speed (1.02 to 1.04 m/s), step time variability, PD rating scale scores, levodopa-equivalent doses, freezing of gait, and fear of falling scores.

Of the original 130 patients, 113 were evaluable at 8 months (55 on rivastigmine; 58 on placebo). The analysis was performed on an intention-to-treat basis, with a primary outcome measure of step variability.

The participants did a normal walk and also were measured while walking doing a simple or a complex cognitive task. The simple task was naming words starting with a specific letter of the alphabet; the more complex cognitive task was alternately naming words starting with either of two different letters of the alphabet.

Using unadjusted values, rivastigmine had a modest but not significant effect on step time variability during normal walking or during walking while performing the simple or the complex cognitive task.

However, once the results were adjusted for cognition, age, previous falls, and baseline gait variability, rivastigmine treatment was associated with less step variability (ie, better performance) upon normal walking or while walking and performing the simple cognitive task.

Walking while doing the more complex cognitive task did not improve. The treatment effect was greatest for normal walking alone, showing a 28% improvement in step time variability.

Table. Rivastigmine Effect on Gait: Adjusted Multivariate Analysisa

Walking Condition Estimated Ratio (95% Confidence Interval)b P Value
Normal walk 0.072 (0.58 - 0.88) .002
Simple cognitive task 0.079 (0.62 - 0.99) .045
Complex cognitive task 0.081 (0.60 - 1.09) .170

aAdjusted for cognition, age, previous falls, and baseline gait variability.

bBack-transformed coefficient for log outcome.

On the secondary outcome of frequency of falls, rivastigmine was associated with 1.4 falls/month compared with 2.4 falls/month with placebo. Rivastigmine did not have a measurable effect on cognition.

Most adverse effects seen in the trial were mild and expected. The number of serious adverse effects occurred equally in the rivastigmine and placebo groups. The most prevalent ones in the rivastigmine group were gastrointestinal disturbance and urinary tract infections.

The investigators noted that strengths of the trial were its high retention rate, the sample size, and the blinded assessment of gait. But it was limited by the use of gait variability as a surrogate for fall risk. However, the secondary outcome of fall frequency as assessed from patient-reported diaries suggested that the association was valid.

Recent work from Parkinson's UK highlighted the fact that a high priority for patients with PD is to stop falls and improve gait and balance. "Falls are very common, and that's devastating to people in terms of fractures and soft tissue injuries and fear of falling, and social isolation all stems from falls," Dr Henderson said.

Nir Giladi, MD, professor and chairman of the Department of Neurology at Tel Aviv Medical Center and the Sackler School of Medicine of Tel Aviv University, Israel, commented to Medscape Medical News that the study was not particularly large but was well designed, albeit preliminary.

"They're missing a lot of information yet, but the preliminary results are quite encouraging that in a patient who is having gait problems, falls, and freezing, if you intervene at the level of the cognitive function you can decrease fall risk, improve mobility, safety, decrease freezing," he said. "It's a very significant observation."

He said that there are very few data from well-controlled prospective studies that can show "that if you intervene at the cognitive level you improve gait, decrease falls, or decrease freezing."

He said only one intervention study, from a group including John Nutt, MD (Neurology. 2010;75:1263-1269), showed that a cholinesterase inhibitor, donepezil, could prevent falls in patients with PD.

Regarding the gait problems while performing a complex cognitive task, Dr Giladi said that patients with PD have limited cognitive reserve, "so if you overload them too much, you are getting significant decrease in function, but they were able to show that at least they performed better on mild cognitive load."

He advised that the investigators need to continue to work on frequency of falls and freezing but also to see whether cognitive aspects have improved "and how does that relate and correlate to the gait changes. So there's a lot to do in terms of analysis."

He said the concept is the most important aspect of the study. "We used to try to prevent falls by physiotherapy, by improving levodopa dose, by giving drug combinations, and we have failed, practically," Dr Giladi said. "The idea to promote or help cognition either by cholinesterase inhibitors — or there are quite a few studies about Ritalin, methylphenidate, as another way to enhance cognition in executive function — is a very important one."

Although this study tested only rivastigmine, he said other drugs or classes of drugs could also provide similar benefit. "That's why I'm saying that the concept is important — to enhance executive function, to improve gait, and decrease falls."

Novartis provided the drug and placebo for the study. Dr Henderson has disclosed no other relevant financial relationships. Dr Giladi serves as a consultant for Teva-Lundbeck, IntecPharma, NeuroDerm, Armon Neuromedical Ltd, and Pharma Two B and has received payment for lectures from Teva-Lundbeck, Novartis, and UCB.

19th International Congress of Parkinson's Disease and Movement Disorders (MDS). Abstract LBA10. Presented June 17, 2015.


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