Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial.

Importance: Carrying a variation in the gene for β-glucocerebrosidase is a major risk factor for Parkinson disease dementia (PDD), and raising β-glucocerebrosidase levels lowers α-synuclein in cell and animals. Ambroxol is a chaperone for β-glucocerebrosidase, which increases the levels of β-glucocerebrosidase. Objective: To examine the safety and tolerability of ambroxol in PDD, test the efficacy of ambroxol in improving or slowing the progression of cognitive deficits, and acquire pharmacological data. Design, Setting, and Participants: This was a 52-week, phase 2, double-blind, placebo-controlled, randomized clinical trial conducted from February 2015 to June 2023. The study took place at a single center and was referral based. Included were patients with PDD who were older than 50 years, had Parkinson disease for at least 1 year before cognitive impairment, had mild to moderate dementia, were taking stable medications, and had a study partner. Interventions: Ambroxol low dose (525 mg per day), high dose (1050 mg per day), or placebo. Main Outcomes and Measures: Safety and tolerability outcomes were adverse events. Primary efficacy outcomes were the Alzheimer Disease Assessment Scale-cognitive subscale, version 13 (ADAS-Cog-13) and Clinician's Global Impression of Change (CGIC). Results: A total of 75 patients were screened, and 55 were randomized. Thirty-one individuals received ambroxol, with 8 patients (mean [SD] age, 78.8 [3.4] years, all male) in the low-dose group and 22 patients (mean [SD] age, 70.7 [7.6]; 19 male [86.4%]) in the high-dose group. One patient was excluded from the high-dose group due to a diagnosis of progressive supranuclear palsy. A total of 24 patients (mean [SD] age, 72.7 [6.3] years; 19 male [79.2%]) were included in the placebo group. Participants receiving ambroxol (23 of 193 adverse events [12%]) showed more gastrointestinal adverse events than those receiving placebo (9 of 172 adverse events [5%]). Statistical analyses compared ambroxol high dose vs placebo. There was no evidence to suggest differences between groups on primary or secondary outcomes. Mean (SD) ambroxol high-dose concentrations were 7.48μM (3.17μM; 95% CI, 6.08-8.87μM) in plasma and 0.73μM (0.07μM; 95% CI, 0.64-0.81μM) in cerebrospinal fluid at the end of titration. Mean (SD) β-glucocerebrosidase levels were higher at week 26 (ambroxol, 12.45 [1.97] nmol/h/mg; 91% CI, 11.54-13.36 nmol/h/mg); placebo, 8.50 [1.96] nmol/h/mg; 91% CI, 7.65-9.34 nmol/h/mg; P = .05) in the ambroxol group compared with placebo. Conclusions and Relevance: Results of this randomized clinical trial reveal that ambroxol was safe, well-tolerated, and demonstrated target engagement. However, the effect of ambroxol on cognition was not confirmed. Trial Registration: ClinicalTrials.gov Identifier: NCT02914366.