Spinal Cord Stimulation for Freezing of Gait in Parkinson's Disease
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 29
- 试验地点
- 1
- 主要终点
- FOG-provoking protocol
研究概览
简要总结
Freezing of gait (FOG) is a severely disabling gait disorder in Parkinson's disease (PD). Its poor response to current therapies reflects the shortfall in current knowledge on its exact pathophysiology. Case series suggest a therapeutic promise of spinal cord stimulation (SCS) for FOG, but double-blind randomised controlled trials with reliable FOG assessments are lacking.
This randomised, double-blind, placebo-controlled cross-over trial aims to define the outcome, safety, optimal stimulation paradigm and underlying mechanism of SCS for FOG in PD, by exploring both clinical and neurophysiological parameters.
Twenty-nine PD patients with refractory FOG will receive an implanted SCS lead connected to an external trial stimulator. During a 3-week trial, 3 stimulation paradigms will be tested in random order, including one sham paradigm. SCS outcome on FOG will be evaluated through wearable accelerometers, self-reported questionnaires and a FOG-provoking protocol at home. Spinal electrophysiological recordings will compare neural properties between PD patients with and without FOG and evaluate intra-patient differences (e.g., on/off medication, DBS states). In patients with deep brain stimulation (DBS) including BrainSense technology, the effect of SCS on pathological beta oscillations in the STN will be explored. A subsequent long-term open-label phase will be conducted in those patients who desire a definitive implanted stimulator.
This project will provide new insights into the pathophysiology of FOG, pave the way for SCS implementation in clinical practice and enhance future patient selection.
详细描述
Freezing of gait (FOG) is a severely disabling gait disorder in Parkinson's disease (PD). FOG leads to falls, anxiety and loss of independence and heavily affects quality of life (QoL). The incidence of FOG increases from 38% in the first 5 years following diagnosis to 65-80% in advanced stages. FOG is a therapeutic challenge, as it often responds poorly to (dopaminergic) pharmacotherapy or deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal pallidum. Likewise, rehabilitation strategies such as gait training achieve small and short term effects at best. The therapeutic response of FOG is far more complex and variable than that of other PD motor symptoms. This reflects the current shortfall in knowledge about FOG pathophysiology, which has drastically impeded adequate therapy development. Furthermore, objective and reliable FOG assessments are challenging and therefore still rarely implemented in clinical trials, limiting the interpretation of the findings. However, recent insight into the underlying mechanisms has resulted in a growing body of literature suggesting a therapeutic promise of spinal cord stimulation (SCS) for FOG.
Spinal cord stimulation is an invasive technique in which specific neuronal circuits are stimulated electrically through spinal epidural electrodes. The stimulation settings can be adjusted to achieve a therapeutic effect, often by eliciting paraesthesia. SCS has been applied mostly in patients with refractory neuropathic pain. Serendipitously, PD patients who underwent SCS to treat comorbid neuropathic pain also noticed a beneficial effect on FOG. This finding led to SCS being further investigated as a therapy for FOG, but despite the encouraging results in animal studies, studies in humans are limited to case reports and series with inconsistent results. Randomised, double-blinded, high-quality trials in large cohorts are much needed for translation to clinical use. Correct blinding in SCS studies was historically impeded by stimulation-induced paraesthesia. However, recent innovations in SCS devices now enable paraesthesia-free stimulation and spinal cord electrophysiology recordings, creating new opportunities for research and trial design.
In addition to the small sample sizes and lack of randomisation and blinding, currently published reports on SCS for FOG lack clear clinical phenotyping of freezing and many also fail to use objective, reliable FOG assessments. Moreover, much remains unknown about the effect of SCS on spinal cord and STN electrophysiology and about optimal stimulation paradigms.
This sham-controlled randomized double-blinded cross-over study aims to define the outcome, safety, optimal stimulation paradigm and underlying mechanism of SCS for FOG in PD patients. Twenty-nine patients will receive a 3-week SCS trial with an implanted lead connected to an external stimulator, during which two SCS paradigms (one with and one without paraesthesia) and a sham paradigm will be compared:
- Tonic SCS (paraesthesia-eliciting)
- DTM SCS (paraesthesia-free)
- Sham SCS (stimulation off)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Both the patient and assessors will be blinded to the SCS paradigm during the core trial. Upon the patient's completion of the core trial (the 3-week trial stimulation period) and after blinded assessment of all videos, the investigator will be unblinded to the patient's treatment response to evaluate the effect of SCS on FOG. This information is critical for determining, in consultation with the patient, whether to proceed with the implantation of a definitive internal neurostimulator or to remove the trial electrode. It is important to note that, as previously stated, the investigator and assessors remain blinded to the patient's assigned SCS paradigm throughout the whole core trial.
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of idiopathic PD in accordance with the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease
- •Optimal medical or DBS management for FOG, as evaluated by a movement disorder neurologist and programming expert. Stable PD medication and/or DBS settings for ≥ 1 month prior to baseline assessment and no changes are expected for the next 8 weeks
- •Self-reported FOG severity of ≥ 1 FOG episode per day, based on NFOG-Q items 1 and 2
- •Presence of FOG during in-hospital clinical assessment consisting of 3 FOG-provoking tasks, in the on-medication state
- •Able to walk 10 meters unassisted without a walking aid (use of a cane is allowed)
- •Able to understand study requirements and provide consent
- •Age 40-79 years inclusive
排除标准
- •Presence of other severe neurological, psychiatric or other disorder that may impede assessment of outcomes
- •Contra-indications to SCS surgery (e.g. epidural fibrosis, inability to safely discontinue anticoagulant drugs, allergy to implants, medically inoperable)
- •Cognitive impairment (Montreal Cognitive Assessment (MOCA) <19/30)
- •Chronic (>6m) severe (numeric rating scale >5/10) back or leg pain, or FBSS, as the antalgic effect of SCS could cloud our interpretations for its effect on FOG
- •Duodopa pump or apomorphine injections
- •Fall frequency >1x/day (this criterion comprises only 'actual falls', no 'near falls')
- •Absence of FOG during preoperative at-home FOG-protocol, in on- or off-medication assessment
- •Pregnancy, lactating or active pregnancy plans
研究组 & 干预措施
Control group 1: SCS patients without PD
± 15 patients without PD who received SCS for FBSS outside research settings.
To evaluate the secondary exploratory outcome on spinal cord electrophysiology in PD freezers, two control groups of SCS patients treated for approved indications outside research settings will be included. This allows for an exploratory, non-blinded, and non-randomized comparison of spinal cord electrophysiological characteristics between patients with PD and FOG (intervention group), without PD (control group 1) and with PD without FOG (control group 2).
干预措施: Spinal electrophysiological recordings (Other)
PD patients with refractory FOG
29 PD patients with refractory FOG will receive a 3-week SCS trial with an implanted lead connected to an external stimulator, during which two SCS paradigms (one with and one without paraesthesia) and a sham paradigm will be compared. If a clinically relevant improvement in FOG or gait is perceived during the external trial stimulation, the participant will receive a permanent implanted neurostimulator.
干预措施: Spinal Cord Stimulation (Device)
Control group 2: SCS patients with PD, without FOG
Max. 5 patients with PD without FOG who received SCS for FBSS outside research settings.
To evaluate the secondary exploratory outcome on spinal cord electrophysiology in PD freezers, two control groups of SCS patients treated for approved indications outside research settings will be included. This allows for an exploratory, non-blinded, and non-randomized comparison of spinal cord electrophysiological characteristics between patients with PD and FOG (intervention group), without PD (control group 1) and with PD without FOG (control group 2).
干预措施: Spinal electrophysiological recordings (Other)
结局指标
主要结局
FOG-provoking protocol
时间窗: Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.
The total percentage time frozen (%TF) of all FOG manifestations across all gait tasks of the FOG-protocol performed in the off medication state, compared between the different SCS paradigms.
次要结局
- FOG-provoking protocol(Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.)
- Safety(6 months)
- Change in Levodopa Equivalent Daily Dose (LEDD)(6 months)
- Changes in home-based gait function(Core-trial: 3 weeks)
- Patient Global Impression of Improvement (PGI-I)(Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.)
- Changes in daily patient-reported FOG severity, falls and near-falls(Core-trial: 3 weeks)
- Change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III and part IV.6(Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.)
- Change in Numeric (Pain) Rating Scale (NRS)(Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.)
- Change in Medication Quantification Scale (MQS)(Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.)
- Change in Parkinson's Disease 39-Item Quality of Life Questionnaire (PDQ-39)(6 months)
- Patient satisfaction(6 months)
- Change in New Freezing of Gait Questionnaire (NFOG-Q)(6 months)
- Change in Characterizing Freezing of Gait questionnaire (C-FOG)(6 months)
- Change in Parkinson Anxiety Scale (PAS)(6 months)
- Change in Beck Depression Inventory (BDI)(6 months)
- Change in Rem Sleep Behaviour Disorder Screening Questionnaire (RBDSQ)(6 months)
- Change in SCales for Outcomes in PArkinson's disease - Autonomic Dysfunction (SCOPA-AUT)(6 months)
- Patient satisfaction(Core-trial: 3 weeks)