Cholinesterase Inhibitors to Slow Progression of Visual Hallucinations in Parkinson's Disease:a Multi-center Placebo-controlled Trial.
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 发起方
- 入组人数
- 91
- 试验地点
- 4
- 主要终点
- time to start with antipsychotic treatment for visual hallucinations
研究概览
简要总结
Rationale: Visual hallucinations (VH) are the most common non-motor symptoms in Parkinson's disease (PD). As an independent predictor for cognitive decline and nursing home placement they form an important disability milestone in the course of PD. According to current clinical guidelines minor VH do not require treatment per se. But as minor VH precede the stage of major VH without insight and PD associated psychosis (PDP) they offer an opportunity for early intervention. Neuroleptic drugs delay the transition into PDP but are unsuitable for early treatment of VH due to their side effects. We hypothesize that cholinesterase inhibitors (ChEI) are a well-tolerated alternative for the early treatment of minor VH to delay the progression to PDP, and that brain network analysis is suitable to predict treatment response.
Objective: Investigate whether early treatment with ChEI delays the progression of minor VH to major VH without insight or PDP. In addition, we will measure motor control, psychotic symptoms, cognitive impairment, mood disorders, daytime sleepiness, adverse events and compliance, disability, caregiver burden and care use. We assess the cost-effectiveness of early chronic treatment of VH with ChEI. Finally, we analyse changes of functional brain networks before and during treatment.
Study design: A randomized, double blind, placebo-controlled, multi-center trial with an economic evaluation.
Study population: 168 patients with PD and VH after fulfilling the in-and exclusion criteria.
Intervention: Rivastigmine capsule 6 mg BID or placebo BID for 24 months.
Main study parameters/endpoints: The primary outcome measure is the median time until PD patients with minor VH progress to major VH without insight. The clinical endpoint is defined as the start with antipsychotic treatment. Secondary outcome measures are changes in motor control, psychotic symptoms, cognitive impairment, mood disorders, daytime sleepiness, cholinergic deficiency, the number of adverse events, compliance, disability and caregiver burden. The median time until PD patients with minor VH progress to PD dementia is measured by means of changes in cognitive function. The secondary neurophysiological outcome measures are peak frequency, functional connectivity, topological network organisation and the direction of information flow. All relevant costs will be measured and valued.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The burden of participation consists of a total of 5 clinical visits (every 6 months), 5 telephone interviews on adverse events during the escalation phase and 9 questionnaires on health related costs (every 3 months). In a subgroup 3 additional visits for EEG recording are needed. There is a risk for adverse reactions with rivastigmine treatment; the most common are nausea and vomiting.
详细描述
The study is performed in four regional study centers: i.e. VUmc-AMC Amsterdam, Atrium MC Heerlen, UMC Groningen en Radboudumc Nijmegen. Each regional study center has a participating neurologist and will station a research nurse - of which some part-time. VUmc-AMC is also national coordinating center and their research nurse is also national trial manager.
Because the logistics are complex and the assessments are cumbersome, it is vital that research nurses perform these to facilitate inclusion and to assure proper follow-up assessments. All research nurses will be trained and examined in performing all aspects of the Visits, i.e. explaining the study and using the questionnaires. Every twelve months, the research nurses will follow additional training to keep their expertise up to date and to minimize intra-rater and inter-rater variability.
In addition to the four study centers, approximately 30 hospitals are requested to participate as local recruitment center. Eligible patients are recruited by the treating neurologist in these recruitment centers during a regular follow-up appointment at the outpatient clinic. In addition, the treating neurologist can send a recruitment letter to a selected group of potentially eligible patients based on data from the patient files or a clinical database. The recruitment letter will give a short introduction on the topic of visual hallucinations and will underline the importance to participate in this study. Patients that are interested are encouraged to contact the research nurse for information or to make an appointment.
The treating neurologist will check the inclusion and -exclusion criteria. He asks the patient for permission to send contact information to the research nurse. If the patient is eligible and agrees, the neurologist will complete the patient registration form with name, gender, date of birth, telephone number and in- and exclusion criteria.
After registration, a research nurse will contact the patient by phone within 10 working days. She will introduce the study to the patient, inform the patient on the gross outline of the trial and discuss the possible benefits and disadvantages. She will answer any additional question about the study. If the patient agrees an appointment will be made (visit 1). All study visits will take place at home or in the outpatient clinic of the regional study center. The study medication is prescribed by the participating neurologist in one of the four regional study centers.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •idiopathic PD with bradykinesia and at least two of the following signs; resting tremor, rigidity, and asymmetry (in accordance with clinical diagnostic criteria of the UK PD Society Brain Bank);
- •the presence of minor VH for at least 4 weeks, defined by a score of 1 or 2 on the hallucinations item of the Unified Parkinson's Disease rating Scale (UPDRS)1-MDS;
- •age 40 years and over.
排除标准
- •Parkinson's Disease Psychosis, defined as the need for antipsychotic drug treatment in the opinion of the treating neurologist;
- •Parkinson's Disease Dementia, defined by a score < 24 on the Mini Mental State Examination (MMSE);
- •current delirium (caused by infection or metabolic disturbance);
- •current treatment with amantadine (Symmetrel) or anti-cholinergics, such as trihexyfenidyl (Artane) or biperideen (Akineton);
- •current or recent (<6 months) treatment with Cholinesterase inhibitor, such as rivastigmine (Exelon) or galantamine (Reminyl);
- •recent (<1 month) change in dopaminergic therapy;
- •history of psychosis or severe ophtalmologic disease (e.g. Charles Bonnet syndrome);
- •permanent stay in a nursing home;
- •no informed consent.
研究组 & 干预措施
Placebo
placebo capsule for oral use 6,0 mg BID during 24 months of follow-up
干预措施: Placebo (for rivastigmine) (Drug)
Rivastigmine
rivastigmine capsule for oral use 6,0 mg BID during 24 months of follow-up
干预措施: Rivastigmine (Drug)
结局指标
主要结局
time to start with antipsychotic treatment for visual hallucinations
时间窗: 24 months
the time until Parkinson's disease patients with minor visual hallucinations progress to major visual hallucinations without insight (according to UPDRS 1 - MDS). The clinical endpoint is defined as the start with antipsychotic treatment.
次要结局
- motor control(24 months)
- psychotic symptoms(24 months)
- cognitive function(24 months)
- cholinergic deficiency(24 months)
- EEG topological network organisation(12 months)
- EEG power analysis(12 months)
- compliance(24 monhts)
- caregiver burden(24 months)
- adverse events(24 months)
- disability(24 months)
- EEG flow direction(12 months)
- EEG frequency band analysis(12 months)
- mood disturbance(24 months)
- daytime sleepiness(24 months)
- care use(24 months)
- EEG functional connectivity(12 months)
研究者
Tom van Mierlo
drs T.J.M. van Mierlo
Amsterdam UMC, location VUmc