Abstract
Objective: Determine if NC001, an oral formulation of nicotine that reduces levodopa-induced dyskinesias (LIDs) in MPTP-Parkinson monkeys, could reduce falls, freezing of gait (FOG), and LIDs in Parkinson disease (PD) patients.Methods: Previously collected data from a study analyzing the effects of NC001 on LIDs in PD patients were reanalyzed. Because indirect-acting cholinergic drugs are sometimes helpful in reducing falls, we hypothesized that NC001, a direct-acting cholinergic agonist, could reduce falls in PD. The original 12-center, double-blind, randomized trial enrolled 65 PD patients. NC001 or placebo was administered 4 times per day for 10 weeks, beginning at 4 mg/day and escalating to 24 mg/day. Assessments included the Unified Dyskinesia Rating Scale (UDysRS) and Parts II-III of the original Unified Parkinson's Disease Rating Scale (UPDRS).Results: Randomization (1:1) resulted in 35 patients on NC001 and 30 on placebo at baseline. Thirty and 27 patients, respectively, had data available for an intent-to-treat analysis. NC001 was safe and well-tolerated. After 10 weeks, NC001 patients (14/30) had a significant reduction in falls vs. placebo patients (3/27) (p = 0.0041) as assessed by UPDRS Part II. NC001 patients (12/30) also had significantly reduced FOG vs. placebo patients (4/27) (p = 0.0043). NC001 patients, compared with placebo patients, had a significant improvement (p = 0.01) in UDysRS ambulation subtest (40% vs. 3%, respectively). Although NC001 patients had a greater reduction in dyskinesias on the UDysRS than placebo patients (30% vs. 19%, respectively), this was not significant (p = 0.09).Conclusions: NC001 significantly improved two refractory symptoms of PD, falls and FOG. The reduction in falls and FOG is attributed to selective stimulation of nicotinic receptors.Clinical Trial Registration: Conducted under IND 105, 268, serial number 0000. ClinicalTrials.gov identifier NCT00957918.
Highlights
Parkinson disease (PD) is a common and disabling neurodegenerative disease
Because indirect-acting cholinergic drugs are sometimes helpful in reducing falls, we hypothesized that NC001, a direct-acting cholinergic agonist, could reduce falls in PD
NC001 patients had a greater reduction in dyskinesias on the Unified Dyskinesia Rating Scale (UDysRS) than placebo patients (30% vs. 19%, respectively), this was not significant (p = 0.09)
Summary
Parkinson disease (PD) is a common and disabling neurodegenerative disease. PD is not curable, many of its symptoms can be managed by dopaminergic drugs, principally levodopa. FOG is often disabling, leads to falls, and is relatively refractory to levodopa [1]. Advancing PD causes more than 30% of patients to fall [3,4,5]. These falls may or may not be associated with FOG [1, 2]. Falls are often refractory to, and sometimes worsened by, levodopa [6]. The dose of levodopa is generally increased as the disease progresses, which results in levodopa-induced dyskinesias (LIDs) in at least 30% of patients [7].
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