Study in Parkinson’s disease of exercise phase 3 (SPARX3): study protocol for a randomized controlled trial
Authors: Patterson Charity G. , Joslin Elizabeth , Gil Alexandra B. , Spigle Wendy , Nemet Todd , Chahine Lana , Christiansen Cory L. , Melanson Ed , Kohrt Wendy M. , Mancini Martina , Josbeno Deborah , Balfany Katherine , Griffith Garett , Dunlap Mac Kenzie , Lamotte Guillaume , Suttman Erin , Larson Danielle , Branson Chantale , McKee Kathleen E. , Goelz Li , Poon Cynthia , Tilley Barbara , Kang Un Jung , Tansey Malú Gámez , Luthra Nijee , Tanner Caroline M. , Haus Jacob M. , Fantuzzi Giamila , McFarland Nikolaus R. , Gonzalez-Latapi Paulina , Foroud Tatiana , Motl Robert , Schwarzschild Michael A. , Simuni Tanya , Marek Kenneth , Naito Anna , Lungu Codrin , Corcos Daniel M. ,   The SPARX3-PSG Investigators, Ellis Terry D. , Shih Ludy C. , Nordahl Timothy J. , Stevenson Michael T. , Alberts Jay L. , Rao Ashwini K. , Landis Corey , Nocera Joe R. , Hackney Madeleine E. , Stegemoller Elizabeth L. , Ridgel Angela L. , Hondzinski Jan M. , Johannsen Neil M. , Drummond Patrick , Milton Heather , Hinkle David A. , Horak Fay B. , Afshari Mitra , Hurt Christopher P. , Kidwell Ariel , Conroy Corinna , Panchal Neil , Schultz Brooke , Marchbank Jes , Bloemer Aaron , Christou Demetra D. , Vaillancourt David E. , Lapierre Stephanie , MacKinnon Colum D. , Amundsen-Huffmaster Sommer , Garland Kristin , Rasmussen Blake B. , Chapman Summer , Spahn Jessica , Wu Laura , Dibble Lee E. , Olivier Genevieve N. , Weltman Art , Dalrymple William Alex , Edwards David , Rynders Corey , Miller Lauren , Earhart Gammon M. , Rawson Kerri S. , Jones Kelvin , Nelles Krista , Almeida Quincy J. , Saint-Hilaire Marie , Factor Stewart A. , Kilbane Camilla , Copeland Brian J. , Dale Marian L. , Espay Alberto J. , Ramirez-Zamora Adolfo , Fessenden Amanda , Deik Andres F. , Camicioli Richard 
Published: October 2022

Abstract
Background
To date, no medication has slowed the progression of Parkinson’s disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline.

Methods
This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60–65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80–85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity.

Discussion
SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health.

Trial registration
ClinicalTrials.govNCT04284436. Registered on February 25, 2020.