Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial

C R A Silveira, J MacKinley, K Coleman, Z Li, E Finger, R Bartha, S A Morrow, J Wells, M Borrie, R G Tirona, C A Rupar, G Zou, R A Hegele, D Mahuran, P MacDonald, M E Jenkins, M Jog, S H Pasternak, C R A Silveira, J MacKinley, K Coleman, Z Li, E Finger, R Bartha, S A Morrow, J Wells, M Borrie, R G Tirona, C A Rupar, G Zou, R A Hegele, D Mahuran, P MacDonald, M E Jenkins, M Jog, S H Pasternak

Abstract

Background: Currently there are no disease-modifying treatments for Parkinson's disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for β-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures.

Methods: This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician's Global Impression of Change (CGIC). Secondary measures will include the Parkinson's disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson's disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes.

Discussion: If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD.

Trial registration: ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.

Keywords: Ambroxol; Cognition; Glucocerebrosidase; Parkinson’s disease dementia; α-Synuclein.

Conflict of interest statement

Ethics approval and consent to participate

The present study has been approved by Western University Health Science Research Ethics Board (Protocol ID: 105234) and all individuals will sign a consent form prior to participation. The study coordinator will review the letter of information, answer questions, and obtain consent from participant and caregiver/next of kin or power of attorney (POA) at the screening visit. Because the ability to consent can be difficult to assess and can change over time, written consent will be obtained from both participants with dementia and caregiver/next of kin or POA to ensure the rights of participants who may have deficits in comprehension or decision making.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Trial flow diagram

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