Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol.
Fabiana Colucci, Micol Avenali, Rosita De Micco, Marco Fusar Poli, Silvia Cerri, Mario Stanziano, Ana Bacila, Giada Cuconato, Valentina Franco, Diego Franciotta, Cristina Ghezzi, Matteo Gastaldi, Antonio Emanuele Elia, Luigi Romito, Grazia Devigili, Valentina Leta, Barbara Garavaglia, Nico Golfrè Andreasi, Federico Cazzaniga, Chiara Reale, Caterina Galandra, Giancarlo Germani, Pierfrancesco Mitrotti, Gerardo Ongari, Ilaria Palmieri, Marta Picascia, Anna Pichiecchio, Mattia Verri, Fabrizio Esposito, Mario Cirillo, Federica Di Nardo, Simone Aloisio, Mattia Siciliano, Sara Prioni, Paolo Amami, Sylvie Piacentini, Maria Grazia Bruzzone, Marina Grisoli, Fabio Moda, Roberto Eleopra, Alessandro Tessitore, Enza Maria Valente, Roberto Cilia
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Abstract
Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA-related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF).
Methods and analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat.
Ethics and dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences.
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