Ambroxol to Slow Progression in Parkinson Disease

Официальное название

Ambroxol to Slow Progression in Parkinson Disease: A Phase IIIa Multi-centre Randomised Placebo-controlled Trial

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Ambroxol Hydrochloride (420mg)
  Oral tablet
• Препарат Placebo
  Oral tablet

Первичные конечные точки

• Change in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I- III score from baseline to Week 104. [Срок оценки: Baseline; Week 104]

Вторичные конечные точки (12)

• 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. [Срок оценки: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.]
• 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. [Срок оценки: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.]
• 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. [Срок оценки: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.]
• 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. [Срок оценки: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.]
• The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) tremor score from baseline to Week 104. [Срок оценки: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.]
• The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) non-tremor score from baseline to Week 104. [Срок оценки: Baseline; Week 20; Week 40; Week 60; Week 80; Week 104.]
• Cognitive impairment using the Montreal Cognitive Assessment from baseline to Week 104. [Срок оценки: At Screening; Baseline; Week 20; Week 40; Week 60; Week 80; Week 104]
• 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. [Срок оценки: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104]
• Symptom improvement from baseline to Week 104 using the Patient Global Impression of Change from baseline to Week 104. [Срок оценки: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104]
• 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. [Срок оценки: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104]
• Non-motor symptoms of PD from baseline to Week 104 , as measured by the Non-Motor Symptoms Scale. [Срок оценки: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104]
• PD progression measured using Parkinson's Disease Comprehensive Response from baseline to Week 104 [Срок оценки: At Baseline; Week 20; Week 40; Week 60; Week 80; Week 104]

Критерии участия

Критерии включения

• 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.
• Adults aged ≥ 35 and ≤ 75 years.
• Hoehn and Yahr stage between 1-2.5, inclusive (in ON stage) at screening visit.
• Known glucocerebrosidase gene (GBA1) status, positive or negative (status MUST be confirmed prior to screening).
• On stable dopaminergic treatment for at least 3 months before enrolment.
• Able and willing to provide informed consent prior to any study related assessments and/or procedures.
• Able and willing to attend trial visits and comply with all study procedures for the duration of the trial.
• Willing and able to self-administer oral ambroxol medication or placebo.

Критерии исключения

• 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.
• Use of an Investigational Medicinal Product (IMP) within 90 days prior to the first dose of trial treatment.
• 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.
• Past surgical history of deep brain stimulation.
• Use of ambroxol in the past 12 months.
• Exposure to Exenatide within 12 months prior to the first dose in this current trial.
• Concomitant medications that in the opinion of the Investigator would preclude participation in the study e.g., exenatide or other GLP1 agonist for diabetes.
• Confirmed dysphagia that would preclude self-administration of ambroxol.
• 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.
• History of known rare hereditary disorders of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
• Presence of the LRRK2 G2019S mutation (status to be confirmed prior to screening).
• History of drug abuse or alcoholism in the opinion of the Investigator that would preclude participation in the trial.
• Pregnant (or planned pregnancy during the trial) and/or breastfeeding.
• 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.
• 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.

• Severe depression defined by a score >20 on the Beck Depression Inventory-II (BDI-II) at screening.
• Significant cognitive impairment defined by a score <20 on the Montreal Cognitive Assessment (MoCA) at screening.
• Use of trihexyphenidyl or benztropine within 30 days prior to the first dose of trial treatment.
• Only applicable for those patients consenting to the optional CSF sub-study: Evidence or history of hypersensitivity to lidocaine or its derivatives.
• 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.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Великобритания · 15 центров

• University Hospitals Birmingham — Birmingham
• Southmead Hospital Bristol — Bristol
• Addenbrookes NHS Trust — Cambridge
• Western General Hospital — Edinburgh
• Kings College London — London
• Royal London Hospital — London
• University College London Hospital's — London
• Newcastle — Newcastle
• … и ещё 7 центров

Идентификаторы

NCT: NCT05778617 · CCTU/2020/365

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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