Ambroxol as a Novel Disease Modifying Treatment for Lewy Body Dementia
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Change in the incidence, nature and severity of AE's and SAE's from baseline
研究概览
简要总结
This is a randomized, placebo-controlled, double-blind study investigating whether the medication Ambroxol is safe,effectiveness and well tolerated for the treatment of Lewy Body Dementia (LBD). Currently the main treatments for patients with LBD target symptom management. However, none of the medications treat the underlying cause of the disease, which includes the accumulation of protein in the brain. Therefore, even if patients respond well to symptomatic treatment, they continue to deteriorate. Therefore, the purpose of the current study is to make sure Ambroxol is safe to take long term and to test the effects of Ambroxol in treating the cognitive impairments associated with LBD by modifying the underlying causes of the disease.
There will be a total of 15 people participating this this study, which will last 52 weeks. Over the study period patients will undergo clinical, neuropsychological and neuroimaging assessment to assess changes.
详细描述
The increasing prevalence of dementia is a serious threat to our medical system and our society. About 500,000 Canadians are affected with dementia, and this number will rise to more than 1 million in the next 20 years. Dementia already costs our economy 15 billion dollars per year. While much of the focus of dementia is on Alzheimer's disease, autopsy studies suggest that up to 30% of dementia is due to diseases caused by abnormal alpha-synuclein accumulation (Synucleinopathies). In healthy brains, alpha-synuclein plays a number of important roles, especially in the process by which brain cells (neurons) communicate. However, when alpha-synuclein abnormally accumulates into clumps inside the neurons it forms Lewy bodies. Eventually, as a result, brain neurons will die causing widespread damage to specific brain regions.
Until the 1980's, cortical Lewy bodies were thought to be relatively rare. However, with improved alpha-synuclein immunostaining techniques, Lewy body dementias are now recognized as the second most common neurodegenerative dementia, after Alzheimer's disease. Lewy body-related disorders include idiopathic Parkinson's disease (PD), Parkinson's disease dementia (PDD) and Lewy Body Dementia (LBD). In LBD, alpha- synuclein accumulation is found in the brainstem, limbic and neocortical regions, giving rise to autonomic, cognitive and motor impairments.
Cognitive Symptoms: Progressive cognitive decline typically begins early in the course of the disease in advance of parkinsonism, but by consensus may follow the development of motor signs up to 1 year. Impaired cognitive domains include executive and visual-spatial functions, attention and short-term memory. For example, patients may have difficulty multi-tasking, following conversations, episodes of staring and perturbed flow of ideas. Regarding short-term memory, patients with LBD experience impairment in memory retrieval, which can be improved by cueing, which is in contrast to memory encoding seen in AD. The early presence of recurrent visual hallucinations is also common in patients with LBD and therefore diagnostically useful. Later in the course of the disease, delusions can be present giving rise to paranoia.
Motor symptoms: Parkinsonian motor signs in LBD are often symmetric, with bradykinesia and gait impairments being more common than resting tremor. Importantly, patients with LBD will often show limited or no response to typical Parkinson's disease pharmacological intervention such as levodopa/carbidopa. LBD patients however do show reduced dopamine transporter activity on single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging.
Other Associated symptoms can include: loss of olfaction, autonomic dysfunction (i.e. neurogenic orthostatic hypotension, constipation, neurogenic urinary frequency and urgency), high sensitivity to medications and rapid eye movement sleep behaviour disorder typically reported by a sleep partner as kicking, punching, yelling and acting out their dreams.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Probable diagnosis of Lewy Body Dementia
- •Age greater than 50 years old
- •Montreal Cognitive Assessment (MoCA) score: 24-18
- •Patients must have a responsible caregiver = 4days/week
- •Must be on a stable dose of medications for parkinsonism (levodopa, dopaminergic agonist) and cognition (cholinesterase inhibitors) and psychiatric (i.e. antidepressants, antipsychotic) for at least 3 months prior to the study
排除标准
- •Evidence of stroke or other neurological condition
- •Any other serious underlying condition or brain disorder that can account in part of in full for the clinical presentation (i.e. cancer or unstable cardiac disease etc.)
- •Contraindication to MRI e.g. presence of metal fragments in head or eye, implanted electrical devices or conductive implants or devices (pacemakers, neurostimulators).
- •Unable to undergo DAT-scan
- •Depression that is, in the opinion of the investigator, significant enough to interfere with neuropsychology and safety assessments
- •Females who are pregnant or breastfeeding, or planning to conceive within the study period
- •Concurrent treatment with oral anticoagulants (including Vitamin K agonists and Novel Oral Anticoagulants (NOACs)) within 4 weeks of screening or anticipated during the 52 week double-blind and open label periods. Specifically, Apixaban, Dabigatran, Edoxaban, Fondaparinux, Rivaroxaban, and Warfarin are prohibited concomitant medications. Exceptions: antiplatelet agents such as Aspirin, Clopidogrel, and Aggrenox.
研究组 & 干预措施
Ambroxol
Participants randomized to the 1350 mg/day group will begin with a dose of 450 mg, increasing bi-weekly to a dose of 1350 mg/day.
干预措施: Ambroxol Hydrochloride (Drug)
Placebo
Participants receive capsules visually identical to the experimental groups but without active ingredients.
干预措施: Placebo (Other)
结局指标
主要结局
Change in the incidence, nature and severity of AE's and SAE's from baseline
时间窗: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
Change in the number of participants with AE's and SAE's
Change in the number of participants with electrocardiogram (ECG) abnormalities
时间窗: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
Change from baseline in the number of participants with clinically significant ECG abnormalities (QT interval) to demonstrate safety
Change from baseline the number of participants with abnormal changes in hemodynamic values while standing
时间窗: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
Changes in hemodynamic values from baseline over time to demonstrate safety
Change from baseline in cerebrospinal fluid (CSF) concentrations of Ambroxol at specified time points
时间窗: Baseline, week 10, week 52
Change in Ambroxol concentrations from cerebrospinal fluid sample from baseline
Change from baseline in plasma concentrations of Ambroxol from blood sample
时间窗: Baseline, week 4, week 10, week 26, week 52
Change in plasma Ambroxol concentrations from blood sample from baseline
Change in Mini Mental State Examination score from baseline over time
时间窗: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
Monitor safety using frequent cognitive evaluations using the mini mental state examination. Lower scores are indicative of worsening cognitive impairment \[score range: 0-30\]
Change from baseline the number of participants with abnormal changes in hemodynamic values while seated
时间窗: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
Changes in hemodynamic values from baseline over time to demonstrate safety
Change in blood analyses from baseline over time
时间窗: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
Change from baseline in number of participants with abnormal changes in clinical laboratory blood tests from baseline over time for safety
Change from baseline in enzyme β-Glucocerebrosidase (GCase) concentration levels in white blood cells
时间窗: Baseline, week 4, week 10, week 26, week 52
Change in white blood cell GCase concentrations from baseline
Change in the number of participants with treatment discontinuations and study discontinuation due to AEs from baseline
时间窗: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
Change from baseline in the number of participants with treatment and/or study discontinuation will be used to demonstrate safety and tolerability
Change in urine analyses from baseline over time
时间窗: Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52
Change from baseline in number of participants with abnormal changes in clinical laboratory urine tests from baseline over time for safety
Change from baseline in enzyme β-Glucocerebrosidase (GCase) concentration levels in CSF
时间窗: Baseline, week 10, week 52
Change in GCase concentration in the CSF from baseline
次要结局
- Change in global brain magnetic resonance imaging atrophy measures(Baseline, week 52)
- Clinician's Global Impression of Change (CGIC)(Baseline, week 26, and week 52)
- Trail making test A and B to assess cognitive function(Baseline, week 26, and week 52)
- Parkinson's disease - Cognitive rating scale to assess cognitive function(Baseline, week 26, and week 52)
- Change in regional brain magnetic resonance imaging atrophy measures(Baseline, week 52)
- Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)(Baseline, week 26, and week 52)
- The Motor subscale of Unified Parkinson's Disease Rating Scale (UPDRS-III)(Baseline, week 26, and week 52)
- Timed Up and Go(Baseline, week 26, and week 52)
- Montreal Cognitive Assessment (MoCA)(Baseline, week 26, and week 52)
- Change in plasma biomarkers(Baseline, week 4, week 10, week 18, week 26, week 34, week 42, week 52)
- Change in Cerebrospinal Fluid (CSF) biomarkers(Baseline, week 10, week 52)
- Neuropsychological Inventory (NPI)(Baseline, week 26, and week 52)
- Geriatric Depression Scale(Baseline, week 26, and week 52)
研究者
Stephen Pasternak
Neurologist
Lawson Health Research Institute