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

本研究的目的是确定高强度耐力运动作为一线治疗的有效性， 最近被诊断患有帕金森病（PD）的人。目前还没有药物被证明可以减缓PD症状的进展，多巴胺能药物也不能使PD的所有症状都受益。因此，PD患者没有足够的治疗来减缓疾病的运动或非运动体征的进展。的 关键的问题是，高强度运动是否有额外的好处， 疾病体征的进展，超出了跑步机训练对一般 健身、步态和功能性活动的参数。临床前数据，人体实验数据，以及 流行病学数据都证明了耐力运动对运动和非运动体征的益处 和疾病的症状，尽管减缓其进展的最佳剂量尚未确定。 我们最近使用无效设计完成了一项多中心II期临床试验，即SPARX研究。我们研究 PD受试者进行中等强度（最大心率（HRmax）的60 - 65%）运动的可行性 高强度耐力运动（80 - 85%HRmax）。参与者尚未开始多巴胺能 药我们证明：1）参与者将在HRmax的80 - 85%之间运动至少6 2）每周至少锻炼3天，3）不良事件较少，4）80- 与等待相比，85% HRmax在运动部分减慢了2.9分 列出通常的护理组，并不认为是徒劳的。这4项调查结果被认为是先验的必要 结果进行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 (two剂量强度），高强度耐力运动的评价者盲法研究。两种剂量的跑步机 中等强度运动（4天/周，每次30分钟，60 - 65%HRmax）和高强度运动（4 天/周，每次30分钟，HR最大值为80 - 85%）。该研究旨在测试3个具体目标。一是 确定高强度耐力运动减缓PD体征进展的疗效， 通过MDS统一帕金森病评定量表（MDS-UMRS第三部分）评分的变化来测量， 6和12个月。第二，确定高剂量耐力与中等剂量耐力的效果 运动对6个月和12个月内PD体征进展的影响，测量指标为：1）6个月内覆盖的距离 1分钟步行，2）每日步数增加，3）认知功能改善，4）最大摄氧量增加，5） 改善生活质量，和6）开始多巴胺能药物治疗的时间和药物治疗的数量。三是 测试12个月以上高强度耐力运动对PD多巴胺能生物标志物的影响， 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。

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.