The Dutch Parkinson GBA Ambroxol trial (DUPARG-AMBROXOL):
A randomised, double-blind, placebo-controlled, single-center trial with Ambroxol in Parkinson patients with a GBA mutation

The pathological cause of Parkinson*s disease (PD) is related to aggregation of
the protein alpha-synuclein (aSyn) in the nervous system. Currently, there are
no therapies available that slow down disease progression, which is the most
important unmet need in PD treatment. The most common genetic risk factor for
PD is a heterozygous mutation of the GBA1 (GBA) gene, encoding the lysosomal
enzyme glucocerebrosidase (GCase). Reduced GCase activity in the brain is
associated with increased levels of aSyn. Ambroxol is mucolytic molecule and
appears to facilitate the refolding of misfolded mutant GCase protein at the
endoplasmatic reticulum, allowing effective trafficking to the lysosome.
Because of these chaperon properties, ambroxol can act as a potential
disease-modifying strategy enhancing the GBA-mediated pathway of aSyn
degradation. Non-clinical studies support the potential for using ambroxol as a
disease-modifying treatment for synucleinopathies such as PD. Studies with
ambroxol in humans so far showed that ambroxol can be safely given in higher
dosages for a longer period. This prospective placebo-controlled trial aims to
determine the effect of ambroxol on the clinical PD motor symptoms of patients
carrying a GBA mutation.

The primary objective is to compare the effectiveness of ambroxol versus
placebo on the MDS-UPDRS part III motor sub-score in the *practically defined
OFF-medication state* in patients with moderate PD, carrying a GBA mutation.
The hypothesis is that ambroxol will be associated with reduced MDS-UPDRS part
III scores at the 60 week time-point after a 12 week washout period.
Secondary objectives will compare the differences at 60 weeks between the
ambroxol and placebo trial arms with respect to:
- Safety and tolerability
- Participant*s prediction of their treatment (ambroxol or placebo) to asses
adequate blinding
- Glucocerebrosidase (GCase) activity in blood mononuclear cells
- Striatal F-DOPA uptake as measured by [18] F-DOPA PET scan
- Relationship between resting-state functional and structural connectivity as
measured by MR imaging and dopaminergic innervation (PET scan)
- Integrity of the nigrostriatal fibers, connecting the substantia nigra and
putamen, using diffusion tensor imaging (DTI) tractography
- Quality of Life (PDQ-39 questionnaire)
- Non Motor Symptoms (NMSS scale)
- Cognition, using the Montreal Cognitive Assessment (MoCA)
- Levodopa dose (LED, Ldopa Equivalent Dose)

This study is designed as a prospective placebo-controlled trial with a washout
design of PD patients carrying a GBA mutation. During a 48 weeks exposure
period, patients will self-administer ambroxol or placebo. At 48 weeks the
ambroxol patients are switched to placebo. Patients however will be kept
blinded during this period. At 60 weeks, baseline measurements will be repeated
followed by study drug withdrawal and a final motor assessment 12 weeks later.
Measurements at baseline, and at 60 weeks consist of: motor assessment in
OFF-medication state, non-motor assessments including neuropsychological
assessment and a quality of life assessment, GCase activity in peripheral blood
mononuclear cells (PBMCs), F-DOPA PET and MRI. Motor assessments will also take
place at 12, 24, 36, 48 and 72 weeks in a defined dopaminergic OFF-state. GCase
activity in PBMCs is also measured at 48 weeks.

Patients will start with oral tablets of Ambroxol 600mg or placebo, which will
increase with 600mg per week, to a maximum of 3 times 600mg a day for a period
of 48 weeks. At 48 weeks all participants will switch to placebo during the
last 12 weeks.

Before inclusion an electrocardiogram (ECG) and a laboratory blood test will be
collected. In total 8 visits will take place in a time period of 72 weeks.
Subjects will undergo 2 longer visits of 5 hours (at baseline and after 60
weeks) including a F-DOPA PET scan, MRI, a blood draw (40 mL), motor assessment
(MDS-UPDRS III), cognitive assessment (MoCA) and two questionnaires. At 12, 24,
36, 48 and 72 weeks follow-up motor assessments (UPDRS III) will take place at
the UMCG or at the patient*s home. At 48 weeks an extra blood draw (40 mL) will
be performed and the ECG and laboratory blood test will be repeated. The burden
of research is related to the radiation burden of PET scans, i.e. F-DOPA PET,
with a total radiation burden is 5,2mSv (with 200MBq injection) and an
additional low-dose CT of 1,5 mSv. The overall radiation burden therefore will
be 13.4mSv in 72 weeks. The expected risk associated with the investigational
treatment is low. Ambroxol is available for adults and children in low doses in
more than 50 countries for over 30 years. Studies in humans have examined
higher doses in a longer period and have shown that ambroxol can be given
safely. However, potential side effects of ambroxol will be recorded
accurately.