Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease: A Randomized Clinical Trial

Abstract

Importance: Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD).

Objective: To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD.

Design, setting, and participants: This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019.

Interventions: A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47).

Main outcomes and measures: The primary end point was change from baseline on the Alzheimer Disease Assessment Scale-Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study-Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography.

Results: Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale-Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score (-3.32 [95% CI, -4.02 to -2.62] for rotigotine and -7.24 [95% CI, -7.84 to -6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and -0.66 [95% CI, -0.80 to -0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group.

Conclusions and relevance: In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living.

Trial registration: ClinicalTrials.gov Identifier: NCT03250741.

Figure 1.. Study Flowchart

Figure 2.. Clinical Data Results

A, The generalized linear mixed model estimated mean change from baseline is shown for the Alzheimer Disease Assessment Scale–Cognitive Subscale (ADAS-Cog-11); scores range from 0 to 70, with higher scores indicating worse cognition. B, The estimated mean change from baseline is shown for the Frontal Assessment Battery (FAB); scores range from 0 to 18, with higher scores indicating better frontal cognitive functions. C, The estimated mean change from baseline is shown for the Alzheimer Disease Cooperative Study Activities of Daily Living scale (ADCS-ADL); scores range from 0 to 78, with lower scores indicating worse function. D, The estimated mean change from baseline is shown for the Neuropsychiatric Inventory (NPI); scores range from 0 to 144, with higher scores indicating worse behavioral symptoms. Baseline is plotted at week 0, which is the mean assessment time of the baseline measurement as offset from the first dose of the trial agent. Error bars indicate standard errors.

Figure 3.. TMS-EEG Results

Changes in global mean field power (GMFP) (A, B) and oscillatory activity (C-F) evoked from the left dorsolateral prefrontal cortex in the rotigotine and placebo groups before and after completion of the trial. The upper panels depict the electroencephalographic activity evoked by transcranial magnetic simulation (TMS) before and after the 24-week period of treatment with rotigotine (A) or placebo (B). The middle panels show changes in oscillatory activity in the group of patients treated with rotigotine (C) and placebo (D), with dark blue indicating lower oscillatory activity; intense red, stronger oscillatory activity; and green, an intermediate value. Panels E and F show the power spectrum profile of evoked oscillatory activity depicted in panels C and D.