Study in Parkinson Disease of Exercise Phase 3 Clinical Trial: SPARX3

运动帕金森病3期临床试验：SPARX3

• 批准号: 10226297
• 负责人: Daniel M. Corcos
• 金额: $ 722.64万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10226297
• 关键词: Adverse event; Aerobic; Animal Model; Attenuated; Binding; Biological Markers; Blood; Brain-Derived Neurotrophic Factor; C-reactive protein; Caregivers; Caring; Clinical; Cognition; Corpus striatum structure; Data; Diagnosis; Disease; Dose; Exercise; Feasibility Studies; Futility; Gait; Goals; Heart Rate; Inflammation; Investigation; Levodopa; Literature; Masks; Maximum Heart Rate; Measures; Moderate Exercise; Motor; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Neurologist; Parkinson Disease; Participant; Patient Self-Report; Persons; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Physiological; Public Health; Quality of life; Randomized; Research Design; Safety; Signs and Symptoms; Site; Specificity; Testing; Therapeutic; Time; VO2max; Waiting Lists; Walking; clinical application; cognitive function; design; dopaminergic neuron; dosage; efficacy trial; endurance exercise; epidemiologic data; exercise prescription; exercise regimen; fitness; human data; improved; neurotrophic factor; pharmacologic; phase III trial; pre-clinical; side effect; translational study; treadmill; treadmill training; treatment as usual

The study objective is to establish the efficacy of high-intensity endurance exercise as first-line therapy for recently diagnosed people with Parkinson's disease (PD). No medications are yet proven to slow the progression of the signs of PD and dopaminergic medications do not benefit all the signs of PD. As such, people with PD have no adequate treatment to slow down the progression of the motor or non-motor signs of the disease. The key question is whether there is an additional benefit of exercising at high-intensity, in terms of slowing the progression of the signs of the disease, beyond the well documented benefit of treadmill training on general parameters of fitness, gait and functional mobility. Preclinical data, experimental data on humans, and epidemiological data all have demonstrated benefits of endurance exercise on the motor and nonmotor signs and symptoms of the disease, although the best dose for slowing down their progression has not been identified. We recently completed a multicenter Phase II clinical trial, the SPARX study, using a futility design. We studied the feasibility of participants with PD performing moderate intensity (60-65% of their maximal heart rate (HRmax)) and high intensity endurance exercise (80-85% HRmax). Participants had not yet started dopaminergic medication. We demonstrated that: 1) participants will exercise at between 80-85% of HRmax for at least 6 months, 2) they will exercise for at least 3 days per week, 3) adverse events are low, and 4) exercising at 80- 85% HRmax slowed progression by 2.9 points on the motor section of the UPDRS when compared to the wait list usual care group and was not deemed futile. These 4 findings were deemed a priori to be the necessary results to proceed to a Phase III efficacy trial. We now propose to conduct a 12-month multi-center, randomized (two doses of intensity), evaluator-masked study of high intensity endurance exercise. The 2 doses of treadmill exercise are moderate intensity (4 days/wk for 30 minutes per session at 60- 65% HRmax) and high intensity (4 days/wk for 30 minutes per session at 80-85% HRmax). The study is designed to test 3 specific aims. First, to establish the efficacy of high-intensity endurance exercise to slow the progression of the signs of PD as measured by the change in the MDS-Unified Parkinson Disease Rating Scale (MDS-UPDRS Part III) score over 6 and 12 months. Second, to ascertain the effect of high dose endurance versus moderate dose endurance exercise on the progression of the signs of PD over 6 and 12 months as measured by: 1) distance covered in 6 minute walk, 2) an increased number of daily steps, 3) improved cognitive function, 4) increased VO2max, 5) improved quality of life, and 6) time to initiate dopaminergic medication and the quantity of medication. Third, to test the effects of high intensity endurance exercise on PD over 12 months on biomarkers of dopaminergic neuronal integrity and blood-derived biomarkers of inflammation, and neurotrophic factors. The study design will facilitate the translation of the study results into a meaningful clinical application of clear therapeutic value.

研究目的是确定高强度耐力运动作为一线治疗的疗效 最近被诊断患有帕金森病 (PD) 的人。目前尚无药物被证明可以减缓帕金森病症状的进展，并且多巴胺能药物并不能改善帕金森病的所有症状。因此，帕金森病患者没有足够的治疗来减缓疾病的运动或非运动症状的进展。这 关键问题是高强度锻炼是否有额外的好处，例如减慢速度 疾病迹象的进展，超出了跑步机训练对一般情况有充分记录的益处 健康、步态和功能活动能力的参数。临床前数据、人体实验数据以及 流行病学数据均表明耐力运动对运动和非运动体征的益处 和疾病症状，尽管尚未确定减缓其进展的最佳剂量。 我们最近使用无效设计完成了一项多中心 II 期临床试验 SPARX 研究。我们研究了 PD 参与者执行中等强度（最大心率 (HRmax) 的 60-65%）的可行性 和高强度耐力运动（80-85% HRmax）。参与者尚未开始多巴胺能 药物。我们证明：1) 参与者将以最大心率的 80-85% 进行锻炼至少 6 次 月，2) 他们每周至少锻炼 3 天，3) 不良事件很少，4) 在 80- 与等待相比，85% HRmax 使 UPDRS 运动部分的进展减慢了 2.9 个点 列出常规护理组并没有被认为是徒劳的。这 4 项发现被认为是先验的必要条件 结果进入 III 期疗效试验。我们现在建议进行一项为期 12 个月的多中心、随机 （两种剂量的强度），高强度耐力运动的评估者掩蔽研究。跑步机的2剂 运动分为中等强度（每周 4 天，每次 30 分钟，最大心率 60-65%）和高强度（4 天/周，每次训练 30 分钟，心率最大值为 80-85%）。该研究旨在测试 3 个具体目标。首先，要 确定高强度耐力运动对于减缓帕金森病症状进展的功效 通过 MDS 统一帕金森病评定量表（MDS-UPDRS 第 III 部分）得分的变化来衡量 6个月和12个月。其次，确定高剂量耐受与中等剂量耐受的效果 锻炼对 6 个月和 12 个月内 PD 症状进展的影响，测量方法为：1) 6 天内行走的距离 分钟步行，2) 增加每日步数，3) 改善认知功能，4) 增加最大摄氧量，5) 改善生活质量，以及 6) 开始多巴胺能药物治疗的时间和药物量。三、至 测试 12 个月内高强度耐力运动对多巴胺能生物标志物对 PD 的影响 神经元完整性和血液来源的炎症生物标志物以及神经营养因子。 研究设计将有助于将研究结果转化为具有明确治疗价值的有意义的临床应用。

项目成果

Re-Addressing Dementia by Network Medicine and Mechanism-Based Molecular Endotypes.

• DOI: 10.3233/jad-230694
• 发表时间: 2023
• 期刊: JOURNAL OF ALZHEIMERS DISEASE
• 影响因子: 4
• 作者: Pachado, Mayra Pacheco;Casas, Ana I.;Elbatreek, Mahmoud H.;Nogales, Cristian;Guney, Emre;Espay, Alberto J.;Schmidt, Harald H. H. W.
• 通讯作者: Schmidt, Harald H. H. W.