1. STEPSS (Stroke Trial for Exercise, Physical function and fitneSS): A Dose Response of Aerobic Exercise Post- Stroke Sandra A Billinger, PT, PhD, FAHA Director, REACH Laboratory Associate Professor Dept of Physical Therapy and Rehabilitation Science KU Medical Center

2. “ If exercise could be purchased in a pill, it would be the single most widely prescribed and beneficial medicine in the nation.” - Robert H. Butler

4. Exercise Prescription Post-Stroke Aerobic Exercise (Billinger, 2014) Frequency – 3-5 days per week – Activity on most days per week Intensity – 40-75% VO 2 peak Time – 20-60 minutes Type

5. Gaps in the Literature for Aerobic Exercise Exercise Prescription Exercise Dose – Minimum or maximum Lack of reporting exercise parameters – Recommendations are largely based on older adults

6. Exercise Prescription Post-Stroke Aerobic Exercise (Billinger, 2014) Frequency – 3-5 days per week – Activity on most days per week Intensity – 40-75% VO 2 peak

7. Exercise Prescription Post-Stroke Aerobic Exercise (Billinger, 2014) Frequency – 3-5 days per week – Activity on most days per week Intensity – 40-75% VO 2 peak Time – 20-60 minutes Type

8. Exercise Prescription Post-Stroke Type

10. Preliminary Evidence for Stroke Exercise Trial 8-week aerobic exercise intervention (3 times per week) – Recumbent Stepper Exercise Parameters : – SBP less than 220 mmHg – DBP less than 105 mmHg – RPE between 12-16/20 – Polar HR Monitor HR Reserve – 50-59% (First 4 weeks) – 60-69% (Second 4 weeks) Outcome Measures – Pre, post-intervention, one-month follow-up – Functional Outcome 6-MWT – Aerobic Fitness HR, SBP, DBP, VO 2 peak, exercise test time, and watts

11. Participants Characteristics n=10 Number or Group Mean (SD) Range Male6 Age (years)61.2 (4.7)52-70 Days Post-Stroke68.6 (40.1)15-123 Overall ABI0.98 (0.11) Fugl-Meyer100.3 (29.3)35-124 Regular Exercisers Pre-Stroke4

12. Outcome Measures Baseline n=9 Post-Intervention n=9 p-value VO 2peak (mL*kg -1 *min -1 ) 15.8 (3.9)17.5 (6.2)0.04 RER1.1 (0.1) 0.44 Work (Watts)66.7 (26.5)83.3 (32.9)0.004 6 MWT304.1 (167.5)342.8 (185.6)0.002

13. Summary for Preliminary Evidence Data from our lab demonstrate – Good adherence from stroke participants – Improvement in outcomes Expand preliminary findings to dose response trial

14. Proposed Study Aim 1: Examine the dose-response of an 8-week aerobic exercise on physical function in individuals 4-9 months post-stroke – We expect that the minimum dose (40% HRR) will provide physical function benefits over 8 weeks and increasing dose will provide additive benefits

15. Proposed Study Aim 2: Examine the dose response of exercise on aerobic fitness – We expect that individuals will demonstrate a dose-response effect of exercise on aerobic fitness (VO 2 peak) – Secondary objective of this aim is to assess whether changes in aerobic fitness are necessary for, and correlated with, changes in physical function

16. Biomarkers for Stroke Recovery Insulin-like Growth Factor (IGF-1) – IGF-1 related to estimated pre-stroke fitness in acute stroke (Mattlage, in press) – Decreases in the IGF-1 ratio within first week related to recovery (Mattlage, 2016) – Exercise increases circulating IGF-1 Vascular Endothelial Growth Factor (VEGF) – Related to endothelial function in acute stroke – Exercise improves endothelial function in subacute stroke (Billinger, 2012) Brain-derived Neurotrophic Factor (BDNF) – Stroke recovery – Exercise (HIIT) beneficial for increasing circulating BDNF BDNF released by contracting skeletal muscle

17. Proposed Study Aim 3: Examine the effect of aerobic exercise on biomarkers of stroke recovery. – Aerobic exercise provides increases in IGF-1, BDNF, VEGF – We hypothesize that increasing exercise doses will result increasing biomarkers of stroke recovery – As a secondary objective, explore whether increases in biomarkers of stroke recovery is related to physical function benefits

18. APPROACH

20. Outcomes Primary 6MWT Peak VO 2 test

21. Outcomes Primary 6MWT Peak VO 2 test Secondary Motor (Fugl-Meyer, 10-meter walk test, grip strength) ADL’s (Physical Performance Test, Frenchay Activities Index) QOL: Stroke Impact Scale Cognitive (Stroop Color Reading, Letter Verbal Fluency, Digit Span F/B) (Vidoni, 2015)

22. Exercise Intensity for CR Fitness Prescription for 8-week intervention – Control group – Karvonen formula % intensity (HR max - HR rest ) +Hr rest Participants will exercise in a target range – 40% HRR – 55% HRR – 70% HRR

23. Accelerometry One week assessment Baseline activity prior to exercise intervention One week prior to testing/follow up visits

24. Research Team at KU Medical Center PI: Sandra Billinger, PT, PhD Co-I – Michael Abraham, MD – Michael Rippee, MD – Jonathan Mahnken, PhD (Statistician) Frontiers Clinical Trial Science Unit (Jeff Burns, MD) – Cognitive Battery Testing – Exercise Testing KU Biospecimen Repository Core Facility Kansas Intellectual and Developmental Disabilities Research Center – Biomarker analyses for all sites

25. FEASIBILITY SURVEY

26. Dose Response of Aerobic Exercise Survey Participants (4-9 months post-stroke) Aerobic exercise trials – Participation, dropout, monitoring Equipment (metabolic gas) – Data output – Calibration – Gas analysis vs flywheel (portable) Testing/Space – Fugl-Meyer, PPT, 6MWT

27. Dose Response of Aerobic Exercise Survey Exercise Type/Modality – Familiar with device – Provide equipment/space Testing and exercise Exercise Staff

28. Summary StrokeNET – Forefront of research for exercise and stroke – Address gaps in the literature (AHA recommendations for exercise) – Move forward biomarker research agenda – Data for Phase III trial Generate data regarding magnitude of exercise-related effect sizes and dose response trends Phase II will inform the choice of the most effective and feasible exercise dose in people post-stroke

29. Questions