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

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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.