GRoningen Early-PD Ambroxol Treatment (GREAT)

GRoningen Early-PD Ambroxol Treatment (GREAT) Trial: A Randomised, Double-blind, Placebo-controlled, Singlecenter Trial With Ambroxol in Parkinson Patients With a GBA Mutation

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.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease; Parkinson
• Intervention / Treatment: Drug: Ambroxol Hydrochloride; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Olav Siemeling; Phone Number: 0031 (0)50 3615639; Email: o.siemeling@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands
    • Recruiting
    • University Medical Center Groningen
    • Contact: Olav Siemeling; Phone Number: 0031 (0)50 3615639; Email: o.siemeling@umcg.nl
    • Principal Investigator: Teus van Laar, Prof. dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; 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).
Experimental: Ambroxol; Ambroxol 1800mg/day	Drug: Ambroxol Hydrochloride; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MDS-UPDRS3 motor scale	Motor scale developed for PD patients, 0-132. 0 means good performance, 132 means very bad performance	60 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability measured by incidence of adverse events and possible side effects	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	all throughout the study. specifically at: 1, 2, 3, 12, 24, 36, 48, 60 weeks
Glucocerebrosidase (GCase) activity in blood mononuclear cells	Measured by the level of sphingolipids in PBMCs	0, 12, 60 weeks
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	Fluctuations in the BOLD signal can be used to investigate the functional architecture and connectivity within the brain.	0, 60 weeks
Quality of Life (PDQ-39 questionnaire)		0, 60 weeks
Non Motor Symptoms (NMSS scale)	minimum value is 0, maximum value is 360. 0 indicating a good performance, 360 indicating a very bad performance	0, 60 weeks
Cognition, using the Montreal Cognitive Assessment (MoCA)	Range is 0-30, 0 indicating the worst performance, 30 indicating the best performance	0, 60 weeks

Collaborators and Investigators

• Sponsor: University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2023
• Primary Completion (Anticipated): July 1, 2025
• Study Completion (Anticipated): July 1, 2025

Study Registration Dates

• First Submitted: March 20, 2023
• First Submitted That Met QC Criteria: April 13, 2023
• First Posted (Actual): April 26, 2023

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Ambroxol; GBA1; GBA
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Respiratory System Agents; Expectorants; Ambroxol
• Other Study ID Numbers: 202100266

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No