A clinical trial of ambroxol in people with Parkinson's disease

Trial ID: ISRCTN93097821

Other - Phase 3 - Recruiting

Background and study aims Parkinson’s disease is a condition in which parts of the brain become progressively damaged over many years and is characterised by the core motor symptoms of tremor, limb rigidity, stiffness, and slowness of movement (bradykinesia). Currently, treatment for Parkinson’s is limited to symptomatic drugs (treating symptoms) with no treatment available that can slow or prevent disease progression. The purpose of this trial is to investigate whether a drug called ambroxol can slow down the progression of Parkinson’s disease and whether it is safe to use over a prolonged period. The researchers want to understand if ambroxol has a beneficial role in Parkinson’s disease through its ability to help increase the activity of an enzyme called GCase, which is thought to be defective in people with Parkinson’s. Who can participate? People who have been diagnosed with Parkinson’s disease within the last 7 years and are between 35 and 75 years old What does the study involve? Participants will be randomly allocated to one of two groups: one group will receive ambroxol and one group will receive. a matching dummy tablet (placebo) which they will take for 2 years, after this all participants will be given ambroxol for 6 months. Questionnaires and neurological assessments, blood tests, a sebum swab (an oily secretion from the upper back), urine samples and stool samples will be required. What are the possible benefits and risks of participating? There is no guarantee that the ambroxol treatment will benefit patients, however, the information we get from the trial will help the trial team find out if ambroxol provides better outcomes for people with Parkinson’s disease and therefore, will improve treatment for all Parkinson’s patients in the future. Although research has shown ambroxol is well-tolerated at the dose given in this trial, there is still a potential chance participants will experience adverse effects related to the trial drug. Common side effects include nausea, numbness in the throat and mouth and changes in sense of taste. Uncommon adverse events include dry mouth, vomiting, dyspepsia, diarrhoea and abdominal pain. Rare adverse events include rash and urticaria. Very rare adverse events include Steven-Johnson syndrome and Lyell's syndrome. The reported frequency of anaphylactic reactions cannot be estimated from the available data. Participants will be informed of all potential adverse events during the informed consent process and they will be advised to monitor and report any side effects in their dosing diaries which will be reviewed by the research team. Participants will undertake a 10-day dose escalation period to mitigate against potential side effects, each stage of the dose escalation period can be extended by further days if adverse events are not tolerable. In addition, telephone calls have been scheduled in between clinic appointments to review any adverse events experienced by participants. All participants will be provided with a patient alert card which details the contact details of the research team in and out of office hours and they will be advised to carry with them at all times. There is currently no adequate data on the use of ambroxol hydrochloride in pregnant women, however, given that it crosses the placental barrier, its use during pregnancy is not recommended, therefore, pregnant women will be excluded from this trial. In addition, as ambroxol is excreted in breast milk, women participants who are breastfeeding will also be excluded from this trial. Male and female participants will be asked to take highly effective contraceptive measures during the course of the trial starting from the time of informed consent and for 2 weeks after their last administration of the trial drug. Serum pregnancy tests for women of childbearing potential (WOCBP) will be performed at the screening visit and urine pregnancy tests for WOCBP will be performed for all subsequent visits, WOCBP participants will also be posted a pregnancy test to use at home 30 days after the last trial treatment. Certain medications are prohibited whilst participating in the ASPro-PD trial because of their possible interaction with ambroxol and/or its proposed mechanism of action. These are detailed in the patient information sheet and research teams will review all concomitant medications before trial entry and at each clinic visit. The GP letter will also include the prohibited medication list. Participants will be required to attend clinic for assessments about every 5 months, three of the visits are in addition to standard-of-care visits. Participants will be reimbursed up to a total of £45 per visit for their travel expenses. For 7 out of the 8 clinic visits, participants will need to attend without having taken their regular PD medication so that they can be assessed in the OFF medication state. Some participants may find this challenging as a result of their symptoms. The trial inclusion criteria have included participants who have a Hoehn Yahr stage of 1 - 2.5 to exclude patients with severe symptoms who may find it extremely challenging to not take their PD medication. The collection of blood samples can be uncomfortable but rarely results in any serious problems. Reported side effects include feeling light-headed or faint, bruising and/or discomfort around the needle site. Every effort will be made to minimise this. Blood samples will be taken at every visit. Participants who have consented to the optional CSF sub-study will have a lumbar puncture on two occasions. Although the lumbar puncture procedure is a safe and routine technique, like any procedure there are some risks associated with it. The most common side effect (less than 10% of cases) is a headache usually developing within 24 to 48 hours of the procedure. It is usually relieved by lying down and can be treated with painkillers such as paracetamol and ibuprofen. Some people experience some lower back pain after a lumbar puncture. In most cases, the pain will ease after a few days and it can be treated with painkillers, such as paracetamol and ibuprofen. A small number (rare) of participants may experience bleeding at the wound site, back discomfort, swelling, rash and itching at the site after the procedure. A very small number (extremely rare) of participants may experience low-pressure headaches, infection, damage to the nerves around the spine and bleeding into the spinal fluid. Participants will be monitored overnight if required. Where is the study run from? University College London (UK) When is the study starting and how long is it expected to run for? July 2024 to December 2030 Who is funding the study? Cure Parkinson's Trust (UK) Who is the main contact? cctu.aspro-pd@ucl.ac.uk

Conditions

• Parkinson's disease
• Nervous System Diseases

Interventions

• Ambroxol hydrochloride

Eligibility

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 state) at screening visit 4. Known glucocerebrosidase gene (GBA1) status, mutant, or wildtype, confirmed prior to the screening visit 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) 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 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: 15.1. Impaired renal function with creatinine clearance <50ml/min at screening visit. 15.2. Moderate or severe hepatic impairment 15.3. 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.

Sponsor

University College London

Source: https://www.isrctn.com/

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