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BMC Neurol. 2019 Feb 9;19(1):20. doi: 10.1186/s12883-019-1252-3.

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

Silveira CRA1,2, MacKinley J1,2, Coleman K1,2, Li Z1,2, Finger E1,2,3, Bartha R4,5, Morrow SA1,2,3, Wells J2,6, Borrie M2,6, Tirona RG2,7, Rupar CA2,8, Zou G9,5, Hegele RA2,10,5, Mahuran D11, MacDonald P3, Jenkins ME2,3, Jog M2,3, Pasternak SH12,13,14,15,16.

Author information

1
Cognitive Neurology and Alzheimer's Disease Research Centre, Parkwood Institute - Main Building, Room A230, 550, Wellington Road, London, Ontario, N6G 0A7, Canada.
2
Lawson Health Research Institute, London, Ontario, Canada.
3
Deparment of Clinical Neurological Science, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
4
Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
5
Robarts Research Institute, Western University, London, Ontario, Canada.
6
Division of Geriatric Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
7
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
8
Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
9
Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
10
Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
11
Laboratory of Medicine and Pathobiology, The Hospital for Sick Children, Toronto, Ontario, Canada.
12
Cognitive Neurology and Alzheimer's Disease Research Centre, Parkwood Institute - Main Building, Room A230, 550, Wellington Road, London, Ontario, N6G 0A7, Canada. spasternak@robarts.ca.
13
Lawson Health Research Institute, London, Ontario, Canada. spasternak@robarts.ca.
14
Deparment of Clinical Neurological Science, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. spasternak@robarts.ca.
15
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. spasternak@robarts.ca.
16
Robarts Research Institute, Western University, London, Ontario, Canada. spasternak@robarts.ca.

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

PMID:
30738426
PMCID:
PMC6368728
DOI:
10.1186/s12883-019-1252-3
[Indexed for MEDLINE]
Free PMC Article

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