Parkinson, Parkinson Disease
Conditions
Keywords
Ambroxol, GBA1, GBA
Brief summary
The most common genetic risk factor for Parkinson's Disease is a heterozygous mutation of the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). Reduced GCase activity is associated with aggregation of the protein alpha synucleine (aSyn) in the central nervous system, which is related to the pathological cause of PD. Ambroxol is a mucolytic expectorant that appears to facilitate the refolding of the misfolded GBA protein thats acts as a chaperone for GCase. This randomized placebo-controlled trial aims to investigate the disease-modifying properties of ambroxol in PD patients with a GBA1-mutation. Patients will undergo motor and cognitive tests, as well as imaging and blood tests.
Interventions
Patients will either receive ambroxol or placebo. ambroxol will be given intially in a dosage of 600mg/day. After 1 week, this will be increased to 1200mg/day. After 2 weeks the maximum dosage of 1800mg/day will be given. In total, ambroxol will be administered for 48 weeks. This is followed by a 12 week washout period, after wich the final outcomes will be measured (week 60).
DRUGPlacebo
Patients will either receive ambroxol or placebo. ambroxol will be given intially in a dosage of 600mg/day. After 1 week, this will be increased to 1200mg/day. After 2 weeks the maximum dosage of 1800mg/day will be given. In total, ambroxol will be administered for 48 weeks. This is followed by a 12 week washout period, after wich the final outcomes will be measured (week 60).
Sponsors
University Medical Center Groningen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Parkinson's disease, according to Movement Disorders Society (MDS) criteria (27) * Disease duration of 10 years or less at time of inclusion * PD patients carrying a GBA1 mutation * Able to write written informed consent, understanding study protocol and perform protocol related actions * Willing and able to self-administer oral ambroxol or placebo medication
Exclusion criteria
* The refusal to be informed about an unforeseen clinical finding * Use of an implanted Deep Brain Stimulation (DBS) system * Confirmed dysphagia that would preclude self-administration of ambroxol or placebo tablets * History of known sensitivity to the study medication * Pregnant or breastfeeding women * Participants of childbearing potential that would not use adequate birth control, consisting of a negative pregnancy test at the screening visit and use of accepted contraceptive methods defined as highly effective while participating in the study * MRI incompatible implants in the body * Any clinically significant or unstable medical or surgical condition that in the opinion of the principal investigator may put the participant at risk when participating in the study or may influence the results of the study or affect the participant's ability to take part in the study, as determined by medical history, physical examinations, electrocardiogram (ECG), or laboratory tests. Such conditions may include: 1. Impaired renal function (a positive urine dipstick test, and laboratory values below or above: a eGFR \<45 ml/min 1,73M2, Sodium 135-145 mmol/L, Potassium 3.5-5.0 mmol/L, Urea 2.5-7.5mmol/L). 2. Moderate/severe hepatic impairment (laboratory values below or above: ASAT 0- 80U/L, ALAT0-90 U/L, GGT \> 80 U/L, Alkaline Phosphatase 35-210 U/L).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MDS-UPDRS3 motor scale | 60 weeks | Motor scale developed for PD patients, 0-132. 0 means good performance, 132 means very bad performance |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glucocerebrosidase (GCase) activity in blood mononuclear cells | 0, 12, 60 weeks | Measured by the level of sphingolipids in PBMCs |
| Striatal F-DOPA uptake as measured by [18] F-DOPA PET scan | 0, 60 weeks | — |
| fMRI resting state to investigate the functional architecture and structural MRI for PET-scan | 0, 60 weeks | Fluctuations in the BOLD signal can be used to investigate the functional architecture and connectivity within the brain. |
| Safety and tolerability measured by incidence of adverse events and possible side effects | all throughout the study. specifically at: 1, 2, 3, 12, 24, 36, 48, 60 weeks | AE will be monitored and patients will be questioned about side effects every week during the first 3 weeks and after that, every 3 months during the visits |
| Non Motor Symptoms (NMSS scale) | 0, 60 weeks | minimum value is 0, maximum value is 360. 0 indicating a good performance, 360 indicating a very bad performance |
| Cognition, using the Montreal Cognitive Assessment (MoCA) | 0, 60 weeks | Range is 0-30, 0 indicating the worst performance, 30 indicating the best performance |
| Quality of Life (PDQ-39 questionnaire) | 0, 60 weeks | — |
Countries
Netherlands
Contacts
Primary ContactOlav Siemeling
Outcome results
None listed