Ambroxol safe but fails to improve cognition in Parkinson’s disease dementia

Treatment with ambroxol in patients with Parkinson’s disease dementia (PDD) is safe and well tolerated but falls short of improving cognition, according to a single-centre phase II study.

The 52-week study included 54 PDD patients who were at least 51 years of age, had Parkinson’s disease for at least 1 year before cognitive impairment, had mild to moderate dementia, and were taking stable medications.

Patients were randomly assigned to receive ambroxol at 525 mg per day (n=8, mean age 78.8 years, all male) or at 1,050 mg per day (n=22, mean age 70.7 years, 86.4 percent male) or placebo (n=24, mean age 72.7 years, 79.2 percent male).

Safety and tolerability were assessed in terms of adverse events (AEs), while the primary efficacy outcomes included the Alzheimer Disease Assessment Scale–cognitive subscale version 13 (ADAS-Cog-13) and Clinician’s Global Impression of Change (CGIC).

A total of 365 AEs were documented, including 193 (53 percent) in the pooled ambroxol group and 172 (47 percent) in the placebo group. Most AEs were mild to moderate in severity. AEs led to treatment withdrawal in eight patients in the ambroxol group and in three in the placebo group (26 percent and 12.5 percent, respectively). Notably, gastrointestinal AEs occurred more frequently in the ambroxol group than in the placebo group (12 percent vs 5 percent). Statistical analyses compared ambroxol high dose vs placebo. There was no evidence to suggest differences between groups on primary or secondary outcomes.

When the high-dose ambroxol group was compared with the placebo group, no significant differences were observed in the efficacy outcomes.

Mean high-dose ambroxol concentrations were 7.48 μM in plasma and 0.73 μM in cerebrospinal fluid at the end of titration. Mean β-glucocerebrosidase levels at week 26 were also higher in the ambroxol vs the placebo group (12.45 vs 8.50 nmol/h/mg; p=0.05).