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1 Presenter Disclosure Information Pamela W. Duncan, PhD, FAPTA, FAHA Multi-Site Phase III Randomized Trial of Physical Therapy Interventions To Improve Walking Recovery Post Stroke FINANCIAL DISCLOSURE: No relevant financial relationship exists

2 Multi-Site Phase III Randomized Trial of Physical Therapy Interventions To Improve Walking Recovery Post Stroke Pamela W Duncan PhD, FAPTA, FAHA Principal Investigator Andrea L Behrman PhD, FAPTA Co-Principal Investigator Katherine J Sullivan PhD, PT, FAHA Co-Principal Investigator for the LEAPS Investigative Team

3 Funding from National Institute of Neurological Disorders and Stroke and the National Center for Medical Rehabilitation Research Trial registration: NCT

4 Why a Trial in Walking Recovery? 800,000 Americans experience a new or recurrent stroke yearly and there are 6.4 million survivors of stroke Rogers V et al, Circulation, Heart and Stroke Statistics 2010: Two-thirds of individuals with stroke have significant limitations in walking Jorgensen H et al Arch Phys Med Rehabil. 1995;76(1):27-32., 75% of stroke survivors fall within six months of the stroke Weerdesteyn V, Arch Phys Med Rehabil 2008: Hip fracture risk is doubled after a stroke Pouwels S et al: Stroke. 2009; Walking speed predicts levels of function Perry J et al, Stroke 1995: ,1995 Schmid A et al Stroke 2007:

5 Walking Speed Predicts Levels of Function and Survival Community mobility requires gait speed > 0.8 m/s Short community walks are feasible at m/s Limited to the home at <0.4 m/s Gait speed is associated with survival in older adults (Studenski et al: JAMA 2011: 50-58)

6 Why this Trial? Body Weight Supported Treadmill Training is an emerging modality to improve walking but there is: Limited evidence to support its value (Cochrane Reviews 2002, 2005) Lack of practice guidelines for training Appropriate dosing and timing of interventions post stroke is unknown Growing consensus in clinical practice that repetitive and progressive practice of stepping using supported treadmill systems is effective Growing commercial market for BWS treadmill systems and robotic-assisted treadmill steppers

7 National Center for Medical Rehabilitation Requests for Proposals To establish best timing, intensity, and duration of stroke rehabilitation therapies Weinrich M, Good D, Reding M, et al. Timing, intensity, and duration of rehabilitation for hip fracture and stroke: report of a workshop at the National Center for Medical Rehabilitation Research. Neurorehabil Neural Repair. Mar 2004;18(1):12-28

8 Primary Study Questions Specifically designed to determine if in addition to usual care Locomotor training program that includes BWST is superior to a home physical therapy program which focused on structured, progressive strength and balance exercises The effect of timing of LTP intervention: Early at 2 months post-stroke vs. Late at 6 months post-stroke Severity: Moderate vs. Severe Limitations in Walking

9 Interventions 1.5 hrs, 3x/wk, 12 wks, structured & progressive programs Locomotor Training Program Home Exercise Program min at 2 mph on TM with BWS Progression: endurance, speed, BWS, independence, adaptability Followed by translation of skills to over ground walking 2-3:1 therapist/patient Strength exercises Balance exercises Progression: repetitions, activity, balance challenge resistance Encouragement to walk daily 1:1 therapist/patient

10 Primary Outcome Measure LEAPS trial definition of improved functional level of walking ability Severe Baseline < 0.4 m/s 1 year post-stroke > 0.4 m/s Moderate > 0.4 m/s < 0.8 m/s > 0.8 m/s Perry J, Garrett M, Gronley JK, Mulroy SJ. Classification of Walking Handicap in the Stroke Population. Stroke 1995;26(6): Schmid A, Duncan PW, Studenski S, et al. Improvements in speedbased gait classifications are meaningful. Stroke.2007;38(7):

11 Prospective Enrollment enrollment dys day post-stroke Initial Initial contact contact & preliminary & preliminary screening screening from inpatient rehab Research Design Secondary screening 7 wks post-stroke Phone call to confirm eligibility Tertiary screen: Exercise tolerance test Baseline assessments 2 mos post-stroke Stratification (severe, moderate) Randomization Early Locomotor Training training 2 mos N = 140 Late Locomotor Training training 6 mos N = 140 Control HEP(C) training 2 mos N = 120 Intervention Type: LTP compared to Control (HEP) Intervention Time: LTP at 2-months or at 6-months post-stroke

12 Subject Recruitment From April 2006 to June 2009 From six inpatient rehabilitation facilities in Florida and California Brooks Rehabilitation Hospital, Jacksonville, FL USC PT Associates, Los Angles, CA and Centinela Freeman Hospital, Inglewood, CA Florida Hospital, Orlando, FL Long Beach Memorial Hospital, Long Beach, CA Sharp Rehabilitation Center, San Diego, CA Rancho Los Amigos National Rehabilitation Center, Los Angeles, CA

13 Primary Inclusion / Exclusion Criteria Age 18 years Stroke within 45 days and living in the community at 2 months post-stroke Residual paresis in the lower extremity Ability to walk 10 feet with no more than 1-person assistance Self-selected 10 meter walking speed less than 0.8 m/s Physician approval for participation Successfully pass an exercise tolerance test Dependent in ADLs prior to stroke Pre-existing neurological disorders Multiple co-morbidities that would be contraindications for exercise programs Inability to travel to treatment site Walking equal to or faster than 0.8 m/s

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15 Baseline at 2 Months Post-stroke Characteristics 62 ±12.7 mean age 45.1% Female 22.1% Black or African American 83% Ischemic 99.5% Modified Rankin 2-4 Mobility Mean walking speed = 0.38 ± 0.22 m/sec 53.4% severe impairment (< 0.4 m/sec) 46.6% moderate impairment (0.4 < 0.8 m/sec) 63.8 days post-stroke at randomization

16 Hypothesis 1 At 1-year post-stroke, there is a significant difference between each of the training groups (LTP-early, LTP-late) and the HEP control group in the proportion of subjects who improve functional level of walking ability. We hypothesized that both the LTP-early and LTP-late groups would be more successful than the Home Exercise (HEP) group.

17 Proportion with Improved Level of Functional Walking Ability(%) Functional Outcome by Group at 12-months OR and 95% CI: 0.83, ( ), P= , ( ), P= % 53.8% 51.6% Early-LTP Late-LTP HEP

18 Hypotheses 2 The improvements in walking speed from baseline to 1-year post-stroke for LTP subjects trained at 2 months will be significantly greater than for subjects trained at 6 months. Results: Early-LTP mean change in comfortable walking speed was 0.23±0.20 m/sec Late-LTP mean change in comfortable walking speed was 0.24±0.23 m/sec No significant interaction between baseline severity of walking impairment and timing LTP for walking speed at 1 year.

19 Walking Speed (m/s) Walking speed trajectory, by intervention group and severity, at screening, 2-(baseline), 6-, and 12-months All post-stroke* Severe Moderate Early-LTP Late-LTP HEP 2mo 6mo 12mo 2mo 6mo 12mo * Screening at 26.0±11.6 days post-stroke. 2-month baseline = point of randomization. The bars indicate 95% confidence interval. Time 2mo 6mo 12mo

20 Walking Speed at 6 Months At 6 months post-stroke, Early-LTP (0.25±0.21 m/sec) and HEP (0.23±0.20 m/sec), groups had similar gains in walking speed and sustained these at 1 year. The Late-LTP group (which only received usual care from 2 to 6 months) improved by 0.13±0.14 m/sec at 6 months.

21 Secondary Outcomes Additional analyses assessed the differences in improvements between the three groups in: Impairment Fugl-Meyer Motor Scores Activity Berg Balance Score Distance walked in 6 minutes ADL/ IADL and mobility Community ambulation (as measured by the step activity monitor Participation (Quality of Life) Stroke Impact Scale Participation Domain

22 Statistically and Clinically Significant Changes in Outcomes from 2 mos to 12 mos post-stroke No differences in improvements across treatment groups HIGHLY clinically relevant improvements Item Comfortable Walking Speed (m/sec) Early-LTP (n=139) Late-LTP (n=143) HEP (n=126) Overall p-value 0.23± ± ± minute Walking Distance (m) 73.2± ± ± Step Activity Monitor (SAM) Median of average number steps/day [25 th - 75 th percentile] 858 [-253, 2422] 1022 [-111, 3009] 1471 [435, 3481] 0.10 Stroke Impact Scale (SIS) Participation (range = 0-100) 17.1± ± ± SIS ADL/IADL (range = 0-100) 9.6± ± ± SIS Mobility (range = 0-100) 13.7± ± ± Fugl-Meyer LE Score (range = 0-34) 1.7± ± ± Berg Score (range = 0-56) 8.0± ± ±

23 Preplanned Secondary Analysis of 6 Month Outcomes Late-LTP (usual care) experienced approximately HALF the improvement of early intervention groups Item Comfortable Walking Speed (m/sec) LTP (n=139) HEP (n=126) UC (n=143) Overall p-value 0.25± ± ±0.14 < minute Walking Distance (m) 81.8± ± ±47.4 < Step Activity Monitor (SAM) Median of average number steps/day [25 th - 75 th percentile] Stroke Impact Scale (SIS) Participation (range = 0-100) 1017 [-102, 2209] 1357 [84, 3382] 566 [-362, 2043] ± ± ± SIS ADL/IADL (range = 0-100) 9.8± ± ± SIS Mobility (range = 0-100) 15.3± ± ± Fugl-Meyer LE Score (range = 0-34) 2.2± ± ± Berg Score (range = 0-56) 8.8± ± ± Activities Specific Balance Confidence Score (range=0-100) 13.8± ± ±

24 Proportion who Improved Functional Level of Walking

25 2mo P12 P24 P36 6mo P12 P24 P36 2mo P12 P24 P36 6mo P12 P24 P36 2mo P12 P24 P36 6mo P12 P24 P36 Walking Distance Walking Speed (m/s) Walking Speed (m/s) Six-Minute Walk Test All Severe Moderate Early-LTP HEP Late LTP (UC) Time Time Time

26 Related Serious Adverse Events 10 related serious adverse events 9 occurred during intervention 3 (2.2%) in early LTP 5 (3.5%) in late LTP 2 (1.6%) in HEP Hospitalizations were for CV symptoms or blurred vision 9 of the 10 participants with related SAEs returned to intervention

27 Minor Adverse Events 56% of participants reported minor adverse events LTP groups reported more events of dizziness and faintness during intervention Early LTP 7.9% Late LTP 5.6% HEP 0%

28 Falls and Falls Rate The most common minor adverse event was falls 57.6% of individuals experienced 1 fall 34% experienced multiple falls 6% experienced an injurious fall More multiple falls in early-ltp group than late-ltp or HEP (p<0.07). Attributable to more multiple fallers in the severe group receiving early-ltp (p< 0.02)

29 Conclusions - Primary Analysis We did not establish the superiority of locomotor training that included BWS on a treadmill and over ground training at either of 2 intervals after stroke over homebased physical therapy that emphasized strength and balance and general encouragement to walk. The home exercise program had fewer risks. The rate of falls suggests that therapy to improve balance, as well as evidence based, multifactor falls prevention programs, should be incorporated into training for walking.

30 Conclusions - Secondary Analysis 6 months Suggest that both programs are effective forms of physical therapy, and at 6 months both are superior to usual care provided according to current standards. Patients recover faster and sustain recovery when the intervention is given early. The patients in the late body-weight supported treadmill and walking program group made significant improvements in walking speed, despite the widely held assumptions and reports that most functional improvements after stroke are complete by six months.

31 LEAPS: in the context of EBP For patients in the first year post-stroke who can walk 10 feet but are not walking at speeds >0.8 m/s (1.8 mph): The randomized trial provides strong and high quality evidence that: Structured progressive locomotor training (including BWSTT) is not superior to a structured strengthening and balance exercise program for walking recovery. Either structured program is more effective than usual care at 6 months post-stroke. A structured exercise program in the home results in fewer adverse events compared to locomotor training.

32 Thank You To the PARTICIPANTS And To the Physical Therapists

33 Duke University Administrative Coordinating Center Pamela W. Duncan, PT, PhD, FAPTA, FAHA Sarah Hayden Mysha Sissine Qiushi Feng, PhD Brooks Rehabilitation Hospital, Jacksonville, FL Deborah Stewart, MD Trevor Paris, MD Joann Gallichio, PT, DSc Florida Hospital, Orlando, FL Mitchell Freed, MD Michelle Dolske, PhD Craig Moore, PT Bettina Brutsch, PT Long Beach Memorial Hospital, Long Beach, CA H. Richard Adams, MD Diehma Hoang, MD Anita Correa, PT Sharp Rehabilitation Center, San Diego, CA Jerome Stenehjem, MD Roxanne Hon, MD Molly McLeod, PT University of Southern California, Los Angeles, CA David Alexander, MD, UCLA Medical Center Julie Hershberg, DPT Samneang Ith-Chang, DPT Centinela Freeman ( ) David Alexander, MD, UCLA Medical Center Julie Hershberg, DPT Samneang Ith-Chang, DPT Rancho Los Amigos National Rehabilitation Center served as a recruitment site in collaboration with the LEAPS site at USC PT Associates, Los Angeles, CA Funding- RO1 NS National Institute of Neurological Disorders and Stroke National Center for Medical Rehabilitation Research NIH Project Officers Scott Janis, PhD, OCR/NINDS Ralph Nitkin, PhD, NCMRR/NICHD Clinical Coordinating Center University of Florida Andrea L. Behrman, PT, PhD, FAPTA Dorian K. Rose, PT, PhD Clinical Coordinating Center University of Southern California Katherine J. Sullivan, PT, PhD, FAHA Julie K. Tilson, DPT, MS Data Management and Analysis Center University of Southern California, Los Angeles, CA Steven Cen, PhD Chris Hahn, MS James Gardener University of Florida, Gainesville, FL Yunfeng Dai, MS Xiaomin Lu, PhD Steering Committee Pamela W. Duncan, PT, PhD, FAPTA, FAHA, Duke University Andrea L. Behrman, PT, PhD, FAPTA, University of Florida Katherine J. Sullivan, PT, PhD, FAHA, University of Southern California Stanley P. Azen, PhD, University of Southern California Samuel S. Wu, PhD, University of Florida Bruce H. Dobkin, MD, University of California Los Angeles Stephen E. Nadeau, MD, University of Florida Sarah K. Hayden, Duke University Consultants Anatole D. Martin, PhD, University of Florida Richard Schofield, MD, University of Florida Medical Safety Monitor Alexander Dromerick, MD, Georgetown University School of Medicine -current Medical Safety Monitor Larry Goldstein, MD Duke University - served as Medical Safety Monitor Sept April 2007 Data Safety Monitoring Board Bruce M. Coull, MD, Chair, University of Arizona, David G. Sherman, MD, served as Chair Elizabeth A. Noser, MD, University of Texas Michael Parides, PhD, Columbia University Steven Wolf, PhD, PT, Emory University

34 Site and Investigative Teams

35 Thank You

36 Equipment Staff Skill HEP may be more Accessible and Feasible LTP HEP Expensive: BWST system and treadmill ($50 to $60 K) 2 to 3 physical therapists/assistants Requires significant training to acquire skills Inexpensive (resistance bands, balls, step blocks) 1 physical therapist No specialized training required for Physical Therapists Location Outpatient only Home or outpatient Compliance Cardiovascular Response Risks Less compliance Higher heart rate response during interventions More intervention-related dizziness and faintness More multiple falls at 1 year in E-LTP Related SAEs rare, were CV related but more observed in More likely comply if delivered in the home Lower heart rate response

37 Hypothesis 1: The functional walking ability (successful recovery of walking ability, walking speed, endurance) will be greater with extended training (increasing dose intervals of 12, 24, and 36 sessions) across all intervention groups. Outcome: Across all groups, 43% of completers leaped a functional level of walking ability by 12 sessions. 13% more leaped by 24 sessions. 7% more leaped by sessions. 37