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. 2024 May 1;24(1):146.
doi: 10.1186/s12883-024-03629-9.

Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation

O Siemeling #  1   2 , S Slingerland #  3   4 , S van der Zee  3   4 , T van Laar  3   4
Affiliations

Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation

O Siemeling et al. BMC Neurol. .

Abstract

Background: To date, no disease modifying therapies are available for Parkinson's disease (PD). Since PD is the second most prevalent neurodegenerative disorder, there is a high demand for such therapies. Both environmental and genetic risk factors play an important role in the etiology and progression of PD. The most common genetic risk factor for PD is a mutation in the GBA1(GBA)-gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). The mucolytic ambroxol is a repurposed drug, which has shown the property to upregulate GCase activity in-vitro and in-vivo. Ambroxol therefore has the potency to become a disease modifying therapy in PD, which was the reason to design this randomized controlled trial with ambroxol in PD patients.

Methods: This trial is a single-center, double-blind, randomized, placebo-controlled study, including 80 PD patients with a GBA mutation, receiving either ambroxol 1800 mg/day or placebo for 48 weeks. The primary outcome measure is the Unified Parkinson's Disease Rating Scale motor subscore (part III) of the Movement Disorder Society (MDS-UPDRSIII) in the practically defined off-state at 60 weeks (after a 12-week washout period). Secondary outcomes include a 3,4-dihydroxy-6-18F-fluoro-I-phenylalanine ([18F]FDOPA) PET-scan of the brain, Magnetic Resonance Imaging (with resting state f-MRI and Diffusion Tensor Imaging), GCase activity, both intra- and extracellularly, sphingolipid profiles in plasma, Montreal Cognitive Assessment (MoCA), quality of life (QoL) measured by the Parkinson's Disease Questionnaire (PDQ-39) and the Non-Motor Symptom Scale (NMSS) questionnaire.

Discussion: Ambroxol up to 1200 mg/day has shown effects on human cerebrospinal fluid endpoints, which supports at least passage of the blood-brain-barrier. The dose titration in this trial up to 1800 mg/day will reveal if this dose level is safe and also effective in modifying the course of the disease.

Trial registration: NCT05830396. Registration date: March 20, 2023.

Keywords: Ambroxol; Disease modifying therapy; GBA1; Glucocerebrosidase; Interventional study; Parkinson’s disease.

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Conflict of interest statement

TvL has received grant support from the MJFF, the UMCG, Menzis, Weston Brain Institute and the Dutch Brain Foundation. Consultancy fees were received from AbbVie, Britannia Pharm., Centrapharm and Neuroderm. Speaker fees were received from AbbVie, Britannia Pharm. and Eurocept.

The remaining authors declare that they have no known competing interests.

Figures

Fig. 1
Fig. 1
Overview of study visits
Fig. 2
Fig. 2
Schematic overview of SL metabolism
See this image and copyright information in PMC

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