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Introduction <p>Genetic studies have identified the <i>GBA1</i> gene as a significant genetic risk factor for Parkinson’s disease (PD), with 10–15% of PD patients carrying <i>GBA1</i> variants. <i>GBA1</i> variants affect the glucocerebrosidase (GCase) enzyme, often leading to reduced GCase activity and associated altered lysosomal function, implicated in PD pathogenesis. Ambroxol, a small molecule widely used for respiratory diseases, has emerged as a potential therapeutic agent for PD, acting by increasing GCase activity. A phase 2 trial demonstrated ambroxol’s safety and efficacy in penetrating cerebrospinal fluid (CSF) and engaging with its target in PD patients, including those with <i>GBA1</i> variants.</p> Methods <p>We present the protocol of the ASPro-PD trial, a phase 3, multicentre, randomised, double-blind, placebo-controlled trial, aimed at evaluating whether high-dose ambroxol improves motor and non-motor function in PD patients. The trial will enrol 330 PD patients with confirmed <i>GBA1</i> status and the primary outcome will be the combined score of parts I, II, and III of the Movement Disorders Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). The secondary outcomes include safety, impact on PD symptoms, and quality of life. Mechanistic and exploratory outcomes include biomarkers related to GCase activity, blood, and CSF biomarkers.</p> Conclusions <p>This trial is the largest to date to study the effect of ambroxol in PD, utilise a genetically stratified PD population and will provide robust estimates of the efficacy of ambroxol in slowing PD clinical progression.</p>

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Protocol of ASPro-PD: a phase 3 trial of ambroxol to slow progression in genetically stratified Parkinson’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月18日

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  • Marco Toffoli,
  • Elisa Menozzi,
  • Mairead Cullen,
  • Kashfia Chowdhury,
  • Saiam Ahmed,
  • Nick Freemantle,
  • Joy Duffen,
  • Richard K. Wyse,
  • Simon R. W. Stott,
  • Helen Matthews,
  • David Dexter,
  • Felicia Ikeji,
  • Julie Moss,
  • Paul Watts,
  • Tom Foltynie,
  • Karl Kieburtz,
  • Olivier Rascol,
  • Werner Poewe,
  • Anthony H. V. Schapira

摘要

Introduction

Genetic studies have identified the GBA1 gene as a significant genetic risk factor for Parkinson’s disease (PD), with 10–15% of PD patients carrying GBA1 variants. GBA1 variants affect the glucocerebrosidase (GCase) enzyme, often leading to reduced GCase activity and associated altered lysosomal function, implicated in PD pathogenesis. Ambroxol, a small molecule widely used for respiratory diseases, has emerged as a potential therapeutic agent for PD, acting by increasing GCase activity. A phase 2 trial demonstrated ambroxol’s safety and efficacy in penetrating cerebrospinal fluid (CSF) and engaging with its target in PD patients, including those with GBA1 variants.

Methods

We present the protocol of the ASPro-PD trial, a phase 3, multicentre, randomised, double-blind, placebo-controlled trial, aimed at evaluating whether high-dose ambroxol improves motor and non-motor function in PD patients. The trial will enrol 330 PD patients with confirmed GBA1 status and the primary outcome will be the combined score of parts I, II, and III of the Movement Disorders Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). The secondary outcomes include safety, impact on PD symptoms, and quality of life. Mechanistic and exploratory outcomes include biomarkers related to GCase activity, blood, and CSF biomarkers.

Conclusions

This trial is the largest to date to study the effect of ambroxol in PD, utilise a genetically stratified PD population and will provide robust estimates of the efficacy of ambroxol in slowing PD clinical progression.