Several patients have completed the 18-month trial and have moved on to the open-label extension, where they will be followed for an additional 12 months.
At the 2023 Alzheimer’s Association International Conference (AAIC), held June 16-20, in Amsterdam, the Netherlands, investigators gave a positive progress report on the phase 2a ANeED study (NCT04588285) assessing ambroxol as a potential therapy for new and early dementia with Lewy bodies (DLB).
Led by Arvid Rongve, MD, PhD, head of the Memory Clinic in Helse Fonna and professor in the Department of Clinical Medicine at the University of Bergen, 38 of the 47 included patients started treatment with compliance that was greater than 90%. Initiated in May 2021, 5 patients thus far have completed the blinded phase after 18 months and have continued on to the open-label phase for an additional 12 months.
The goal for the multicenter, placebo-controlled trial is to include 180 participants who are randomly assigned 1:1 to either ambroxol 1260 mg/d or placebo for an 18-month period. As of February 2023, 6 of the 7 sites have started recruitment. In the 47 patients with available data, the mean Mini-Mental State Examination (MMSE) scores at baseline were 23.5 (SD, 4.4) and mean Unified Parkinson’s Disease Rating Scale Part III scores were 21.2 (SD, 12.7).
The mean age of those included was 71.3 (SD, 6.1) years with a mean disease duration of 9.9 (SD, 9.2) months. Thus far, the reported adverse events included falls, nausea, and sleep disturbances; however, the relationship of these with ambroxol remains uncertain.
Ambroxol is a mucolytic compound and the main ingredient of over-the-counter cough medicines sold in many countries. The hypothesis that ambroxol could potentially be useful in DLB originated in studies in Gaucher disease, a lysosomal storage disorder, caused by a mutation in the glucocerebrosidase (GCase) gene and resulting in the development of parkinsonism in some patients. This has led researchers to discover that mutations in the GBA1 are a genetic risk factor for synucleinopathies similar to Parkinson disease and DLB.2
Research has shown that patients with PD and DLB without GCase mutation also exhibit lower levels of GCase activity in the central nervous system, which is related to earlier disease onset and worse cognitive and nonmotor symptoms. This suggests a potential contribution of the GCase activity in disease pathogenesis, possibly by alteration of lysosomal function.
In the ongoing ANeED study, prior to randomization, patients are stratified on risk factors, including number of apolipoprotein (APOE) e4 alleles and levels of amyloid-ß in cerebrospinal fluid (CSF). The primary outcome is change in the mean score on MMSE-N3 at 18 months, with secondary outcomes that include safety and tolerability, as well as subgroup analyses. In addition, investigator will assess the effect of ambroxol on neuropsychological tests and global functional decline, as measured by changes in Clinical Dementia Rating-Sum of Box scores.3
The trial is also unique in that there are several optional sub-studies within it. One such analysis will characterize rsEEG parameters in patients with DLB and compare them with Alzheimer disease (AD) and healthy age matched controls from the European DLB Consortium EEG database. In addition, a neuroimaging study using cerebral MRI anatomical neuroimaging scans without contrast will be carried out on either 1.5 or 3T scanners depending on site.
CSF fluid and blood biomarker studies will also take place in ANeED, testing to see if ambroxol has an effect on brain amyloidosis, tau tangles, and neurodegeneration. Investigators also are planning on assessing caregiver stress levels to identify which critical moments in patient care lead to distress. The trial also has remote monitor aspects as well. High-tech digital methods, such as smartphones, smart glasses, smart headbands, and non-contract smart sleep monitor will be used to register the spectrum of vital signs, sleep parameters, motor activity, and eye tracking.