Clinical trial NCT05778617: Ambroxol to Slow Progression in Parkinson Disease
Official title: Ambroxol to Slow Progression in Parkinson Disease: A Phase IIIa Multi-centre Randomised Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Parkinson Disease
Keywords: Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Ambroxol
Synucleinopathies
Lead sponsor: University College, London
Sponsor class: OTHER
First posted: 2023-03-21
Enrollment: 330
Sex: ALL
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomised, double blind, parallel group, placebo controlled, Phase 3a trial of daily ambroxol hydrochloride (420mg) as a potential disease modifying treatment for Parkinson's disease.
Primary purpose: TREATMENT

Brief summary: This is a UK only clinical trial in patients with Parkinson's disease (PD) of a drug called ambroxol hydrochloride, which is an already licensed drug for the treatment of respiratory conditions (such as a common cold) in many European countries. The aim of this trial is to find out whether ambroxol hydrochloride can slow down the progression of Parkinson's disease and to evaluate it's safety and tolerability.

Detailed description: This is a 104-week, randomized, double-blind, multi-centre, parallel group, placebo-controlled clinical trial of ambroxol hydrochloride in patients with PD, with a 26-week open-label extension phase. Participants will undergo screening to evaluate their eligibility to participate in the trial. All eligible participants will be randomised to receive either ambroxol hydrochloride (420mg) or it's matching placebo in a 1:1 ratio three times a day for 104 weeks, including a 2-week dose escalation period. Once the end of the blinded treatment has been reached, all participants will enter the open-label extension phase and will receive ambroxol hydrochloride (420mg) three times a day for 26 weeks, including a 2-week dose escalation period. All clinical staff, study investigators, and participants will be blinded to study assignments throughout the entirety of the trial.

There will be an optional sub-study including 106 participants in which a cerebrospinal fluid (CSF) sample will be taken on two occasions via a Lumbar Puncture procedure to measure ambroxol drug levels, assess whether the glucocerebrosidase enzyme has been stimulated and the levels of other substances thought to be associated with the development of PD and confirm whether the study drug has penetrated the cerebrospinal fluid and Central Nervous System.

Eligibility criteria: Inclusion Criteria:

1. A diagnosis of Parkinson's disease (in accordance with the MDS diagnostic criteria) within 7 years of the screening visit confirmed by year of diagnosis.
2. Adults aged ≥ 35 and ≤ 75 years.
3. Hoehn and Yahr stage between 1-2.5, inclusive (in ON stage) at screening visit.
4. Known glucocerebrosidase gene (GBA1) status, positive or negative (status MUST be confirmed prior to screening).
5. On stable dopaminergic treatment for at least 3 months before enrolment.
6. Able and willing to provide informed consent prior to any study related assessments and/or procedures.
7. Able and willing to attend trial visits and comply with all study procedures for the duration of the trial.
8. Willing and able to self-administer oral ambroxol medication or placebo.

Exclusion Criteria:

1. Participation in another interventional clinical trial of an Investigational Medicinal Product (IMP) and use of an Investigational Medicinal Product (IMP) within 90 days prior to the first dose of trial treatment.
2. Use of an Investigational Medicinal Product (IMP) within 90 days prior to the first dose of trial treatment.
3. Participation in another clinical trial of an Investigational New Drug being tested for PD disease modifying potential within 12 months prior to the first dose of trial treatment.
4. Past surgical history of deep brain stimulation.
5. Use of ambroxol in the past 12 months.
6. Exposure to Exenatide within 12 months prior to the first dose in this current trial.
7. Concomitant medications that in the opinion of the Investigator would preclude participation in the study e.g., exenatide or other GLP1 agonist for diabetes.
8. Confirmed dysphagia that would preclude self-administration of ambroxol.
9. History of known sensitivity to the study medication, ambroxol or its excipients (lactose monohydrate, granulated microcrystalline cellulose, copovidone and magnesium stearate) in the opinion of the investigator that contraindicates their participation.
10. History of known rare hereditary disorders of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
11. Presence of the LRRK2 G2019S mutation (status to be confirmed prior to screening).
12. History of drug abuse or alcoholism in the opinion of the Investigator that would preclude participation in the trial.
13. Pregnant (or planned pregnancy during the trial) and/or breastfeeding.
14. Women of childbearing potential (WOCBP) and male participants with a partner of childbearing potential not willing to use highly effective contraception or abstinence for the duration of the trial treatment and for 2 weeks following the last dose of the study drug.
15. Any clinically significant or unstable medical or surgical condition that in the opinion of the Investigator may; put the participant at risk when participating in the study, influence the results of the study or affect the participants ability to take part in the study, as determined by medical history, physical examinations, electrocardiogram (ECG) or laboratory tests. Such conditions may include:

    A. Impaired renal function with creatinine clearance \<50ml/min at screening visit.

    B. Moderate/Severe hepatic impairment.

    C. A major cardiovascular event (e.g., myocardial infarction, acute coronary syndrome, compensated congestive heart failure, pulmonary embolism, coronary revascularisation) that occurred within 6 months prior to the screening visit.
16. Severe depression defined by a score \>20 on the Beck Depression Inventory-II (BDI-II) at screening.
17. Significant cognitive impairment defined by a score \<20 on the Montreal Cognitive Assessment (MoCA) at screening.
18. Use of trihexyphenidyl or benztropine within 30 days prior to the first dose of trial treatment.
19. Only applicable for those patients consenting to the optional CSF sub-study: Evidence or history of hypersensitivity to lidocaine or its derivatives.
20. Only applicable for those patients consenting to the optional CSF sub-study: current treatment with anti-coagulants (e.g., warfarin) that might preclude safe completion of the lumbar puncture in the opinion of the Investigator. Aspirin will be permitted.
21. Only applicable for those patients consenting to the optional CSF sub-study: Significant known lower spinal malformations or other spinal abnormalities that would preclude a lumbar puncture.

Primary outcomes:
measure: Change in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I- III score from baseline to Week 104.
timeFrame: Baseline; Week 104
Secondary outcomes:
measure: Motor signs of PD using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score in the OFF medication state from baseline to Week 104.
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.
measure: Motor complications of PD using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part IV score in the ON medication state from baseline to Week 104.
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.
measure: The non-motor impact of PD on patients using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part I score in the ON medication state baseline to Week 104.
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.
measure: The motor aspect impact of PD of patients experiences on daily living using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II score in the ON medication state from baseline to Week 104.
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.
measure: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) tremor score from baseline to Week 104.
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.
measure: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) non-tremor score from baseline to Week 104.
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.
measure: Cognitive impairment using the Montreal Cognitive Assessment from baseline to Week 104.
timeFrame: At Screening; Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Patient reported measure of health status and quality of life using the Parkinson's disease 39 item Quality of Life questionnaire from baseline to Week 104.
timeFrame: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Symptom improvement from baseline to Week 104 using the Patient Global Impression of Change from baseline to Week 104.
timeFrame: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Quality-of-Life outcome differences between the two treatment groups from baseline to Week 104, as measured by the descriptive system for health-related quality of life, EQ-5D-5L.
timeFrame: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Non-motor symptoms of PD from baseline to Week 104 , as measured by the Non-Motor Symptoms Scale.
timeFrame: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: PD progression measured using Parkinson's Disease Comprehensive Response from baseline to Week 104
timeFrame: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Assessment of postural instability and falls from baseline to Week 104 using the Dresden Falls Questionnaire.
timeFrame: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Symptom severity, treatment response and the efficacy of treatment from baseline to Week 104 using the Clinical Global Impression of symptom severity and improvement scales.
timeFrame: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in pulse (bpm) from baseline to Week 104
timeFrame: At Screening; Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in blood pressure (mmHg) from baseline to Week 104
timeFrame: At Screening; Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in temperature (°) from baseline to Week 104
timeFrame: At Screening; Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in respiratory rate (breaths per minute)from baseline to Week 104
timeFrame: At Screening; Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Body Mass Index (weight and height will be combined to report BMI in kg/m^2) from baseline to Week 104
timeFrame: At Screening; Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Red Blood Cell Count (10^12/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Haemoglobin (g/dL) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Haematocrit (%) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Platelets (10^9/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in White Blood Cell Count (10^9/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Neutrophils (10^9/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Eosinophils (10^9/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Basophils (10^9/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Lymphocytes (10^9/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Monocytes (10^9/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Urea (mmol/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Sodium (mmol/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Potassium (mmol/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Creatinine (µmol/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Total Bilirubin (µmol/L)from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Alkaline phosphatase (IU/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Alanine transaminase (IU/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Aspartate Aminotransferase (IU/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Uric Acid (mg/dL) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Bicarbonate (mmol/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by changes in Chloride (mmol/L) from baseline to Week 104
timeFrame: At Screening; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Safety and tolerability of ambroxol hydrochloride as indicated by the occurrence / severity of treatment related Adverse Events assessed by CTCAE v5.0 from baseline to Week 104
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Time to initiation of rescue medication
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Change in levodopa equivalent dose at 104 weeks
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
Other outcomes:
measure: The association between ambroxol, the glucocerebrosidase enzyme and other proteins associated with the development of PD measured by glucocerebrosidase enzyme activity and other protein markers in blood and cerebrospinal fluid (CSF) samples.
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: The association between ambroxol and alpha-synuclein levels in blood and cerebrospinal fluid (CSF) samples from baseline to Week 104.
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: The association between ambroxol and glycerylceramide, neurofilament light chain and lipid levels in cerebrospinal fluid (CSF) samples from baseline to Week 104.
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104
measure: Affect of GBA status on all measurement outcomes for both treatment arms from baseline to Week 104.
timeFrame: Baseline and Week 104
measure: Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I- IV score from baseline to Week 130.
timeFrame: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104; Week 130
measure: Comparison of change in the gut microbiome composition from baseline to Week 104.
timeFrame: Baseline and Week 104.
measure: Comparison of The Smell Identification Test [UPSIT] score change from baseline to week 104.
timeFrame: Baseline and Week 104.
Locations:
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham
city: Bristol
country: United Kingdom
facility: Southmead Hospital Bristol
city: Cambridge
country: United Kingdom
facility: Addenbrookes NHS Trust
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: London
country: United Kingdom
facility: Kings College London
city: London
country: United Kingdom
facility: Royal London Hospital
city: London
country: United Kingdom
facility: University College London Hospital's
city: Newcastle Upon Tyne
country: United Kingdom
facility: Northumbria
city: Newcastle
country: United Kingdom
facility: Newcastle
city: Oxford
country: United Kingdom
facility: The John Radcliffe Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Salford
country: United Kingdom
facility: Fairfield General Hospital
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Wales
country: United Kingdom
facility: Prince Philip Hospital
Study officials:
affiliation: University College, London
name: Anthony Schapira
role: PRINCIPAL_INVESTIGATOR
References: