Efficacy of Community-Based Exercise Therapy Among African American Patients With Peripheral Artery Disease

This randomized clinical trial assesses whether provision of educational materials with motivational interviewing or with Patient-Centered Assessment and Counseling for Exercise improves walking performance in African American patients with peripheral artery disease.

African Americans with PAD Version 6.0, October 2012 and lower limb blood flow (as measured by the ankle brachial index -ABI). Our 48 comparison group will receive the same print material as the two interventions as well 49 as contact every three months to update any changes in contact information and to 50 assess their health status. We will randomize 204 participants to one of three arms: 51 Control (Tx1); PACE (Tx2); or MI (Tx3). In addition, we will determine the efficacy of 52 PACE (Tx2) to increase walking distance in AAs with PAD, compared to Control (Tx1). 53 54 Primary Hypothesis: 55 1. At 6 months, AAs with PAD randomized to MI (Tx3) will have a greater increase in 56 their walking distance, compared to those receiving PACE (Tx2) and the control group 57 (Tx1). 58 59 Secondary Hypotheses: 60 1. AAs with PAD randomized to MI (Tx3) will have a greater increase in their walking 61 distance at 12 monthsa follow-up period beyond the six months of active intervention 62 compared to those receiving PACE (Tx2) and compared to the control group (Tx1). 63 2. At 6 and 12 months, AAs with PAD randomized to MI (Tx3) will have a greater 64 increase in their home-based walking and their lower limb blood flow, compared to 65 those receiving PACE (Tx2) and to the control group (Tx1). 66 3. At 6 and 12 months, AAs with PAD randomized to PACE (Tx2) will have a greater 67 increase in their walking distance compared to those randomized to control (Tx1). 68 69 Exploratory Aim: 70 We will explore potential mediators (self-efficacy, social support, intrinsic/extrinsic 71 motivation) and moderators (co-morbidities, leg symptom type, stage of change) of 72 intervention effects on walking distance, home-based walking, and lower limb blood flow 73 among AAs with PAD. 74 75 2. METHODS 76 77 Research Study Design: 78 We will conduct a 12-month, 3-arm randomized trial to determine the benefits of the 6-79 month long MI intervention -and culturally sensitive print materialin African 80 Americans with PAD.

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Pilot Study 83 The principal investigator was a faculty member at the University of Minnesota in Year 1 84 of the study. The pilot study was completed in Year 1. The pilot study served to assist 85 the study team with recruitment strategies and to further develop the culturally sensitive 86 print material. During the first year of the project, staff created and worked 87 collaboratively with the Scientific Advisory Board and the Community Advisory Board to 88 evaluate and advise regarding the components and delivery of the intervention and to 89 prepare for the intervention clinical trial.

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Clinical Trial 92 Year 2 -5 will include the full trial, data analysis, and completion of initial manuscripts. 93 Below, the study flow is outlined. 94 Step 1. Telephone Screening 95 For the initial step to assess eligibility, research staff will conduct a telephone screen of 96 each potential participant. During the telephone interview, study staff will review the 97 exclusion checklist and administer the Physical Activity Readiness Questionnaire (PAR-98 Q). The research staff will also gather contact information, demographics, and any co-99 morbidities (e.g. arthritis, COPD, asthma, angina, diabetes, and hypertension). 100 • The PAR-Q, developed by Canadian exercise experts, is a valid and proven tool 101 for screening individuals prior to initiation of physical activity. The questionnaire 102 detects relevant problems that may require further evaluation by a physician prior 103 to starting any form of exercise. 104 • Patient-centered Assessment and Counseling for Exercise (PACE) assessment 105 protocol will be used to identify persons who are in the Stage of Action (score in 106 the range of 5 to 8). As noted in the exclusion criteria and given our focus on 107 sedentary persons, we will exclude persons at such high levels of activity. 108 109 Step 2. In-Person Screening Examination 110 To determine if a participant has PAD, study staff will perform an ankle brachial index 111 (ABI; a sensitive measure to diagnose PAD) and administer the Short Physical 112 Performance Battery (SPPB) during the initial in-person visit. If the participant has PAD, 113 he/she will complete a treadmill test. Each participant will also receive a culturally 114 sensitive handbook for managing PAD and a pedometer.

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The ABI may be done during mass screening events such as public health fairs or 117 events at churches. Consent to join the study will not be obtained at these events. The 118 test will be explained to anyone who approaches the booth and their verbal agreement 119 to have the test done will be considered consent. If the results of the ABI test indicate 120 the individual qualifies for the study, the study will be explained to them. If they are 121 interested in joining the study, they will be asked to schedule an appointment to come in 122 for the SPPB. Full study informed consent will be obtained at that visit.

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There may also be situations where a potential participant contacts the study team with 125 an interest in joining the study but cannot easily leave their home. In this event, the 126 study team will go to the participant's home and perform the ABI test and the SPPB. A 127 screening consent form has been developed for this situation. The study team will 128 review this one page document with the potential participant and they will be asked to 129 sign before any study activities are performed. If the participant passes this stage of 130 screening and wishes to continue into the study, travel arrangements will be made for 131 them to come in for the treadmill test. 132 133 • Ankle-Brachial Index (ABI): Eligibility and Secondary Outcome: A participant will 134 rest for 5 minutes and a 5 or 8 MHz hand-held Doppler will be used to measure 135 systolic blood pressures in both brachial arteries and in both ankles (i.e., the 136 dorsalis pedis and posterior tibial arteries). The resting ABI will be calculated 137 based on the ratio of the ankle and arm pressures. For each leg, the ankle 138 pressure will be the higher of the dorsalis pedis and posterior tibial artery systolic 139 blood pressures. The arm pressure will be the higher of the right and left brachial 140 systolic pressures. The leg with the lowest ABI will be the determining cut-point 141 for defining disease. The ABI will be assessed at baseline and again at the 12-142 month follow-up visit. We will provide baseline training (10 hours) to all study 143 staff, and refresher training every 6 months. Random fidelity checks of the staff 144 will be performed by Dr. Collins. 145 • Short Physical Performance Battery (SPPB): This assessment is a powerful 146 predictor of disability and mobility. The patient will be asked to do a series of 147 timed-functional tasks. They will first be asked to attempt three balance tests, 148 starting with their feet together (side by side) for 10 seconds. Then they will be 149 asked to do semi-tandem stand (heel of one foot placed by the big toe of the 150 other foot which they may put either foot in front, whichever is more comfortable 151 for them) for 10 seconds. Final test is tandem stand (heel of one foot in front of 152 and touching the toes of the other foot) for 10 seconds. If participant is unable to 153 hold the position for each of the balance tests for 10 seconds, record result and 154 move to gait speed test. For the gait speed test, the participant will be asked to 155 walk 13 feet and one half inch at their usual speed, just as if they were walking 156 down the street to go to the store. Lastly, the participant will be asked to fold their 157 arms across their chest and sit, so that their feet are on the floor then stand up 158 keeping their arms folded across their chest. If the participant is able to complete 159 the initial chair stand, they will be asked to complete five continuous chair stands 160 without using their arms. All of the functional tests are timed and scored based 161 on the time. If the SPPB is not performed in the home as indicated above, the 162 participants will complete this testing at KUMC-Wichita. Participants will be given 163 parking directions and a map to indicate where this appointment will be held. 164 • Submaximal Exercise Treadmill Test: Clinical Safety to Engage in a Walking 165 Program: PAD is a marker for atherosclerosis in other vascular beds, most 166 notably the coronary arteries. Although many patients do not have significant 167 coronary artery disease limiting daily activities, it is imperative to identify 168 individuals who may experience exercise-induced coronary ischemic symptoms, 169 or clinically silent exercise-induced ST depression > 2.0 mm, for whom study 170 inclusion would be contraindicated. We will conduct a symptom-limited exercise 171 test also known as a sub-maximal test. We will use an exercise treadmill test 172 with 12-lead electrocardiographic monitoring and measurement of blood 173 pressure. This graded exercise treadmill test requires a constant treadmill speed 174 with modest increases in grade every few minutes. Specifically, the treadmill test 175 will begin at 2 mph per participant's comfort level. The speed of the treadmill test 176 may be reduced to no less than 1.5 mph. The incline increase will be a 2% 177 increase of incline every 2 minutes. For participant's recovery, return to baseline 178 vitals is the goal with a maximum time of 20 minutes. Following a demonstration 179 by study staff, the patient will walk on a treadmill to maximal walking distance. 180 During testing, patients will rate leg discomfort and rate of perceived exertion. 181 Leg discomfort will be based on a scale of 1 to 4: 0=no pain, 1=onset of pain, 182 2=mild pain, 3=moderate pain, and 4=severe pain. Rate of perceived exertion will 183 be based on the Borg scale. For the purposes of the study, the participant will be 184 excluded if they cannot walk for a minimum of two minutes or if they have a Short 185 Physical Performance Battery score of 11 or higher. If a participant is unable to 186 complete two minutes on the treadmill on their first try, they will be asked to come 187 back once to try the test again. This treadmill test will take place at a separate 188 visit from the ABI and SPPB. Participants will be asked to come to Heartland 189 Cardiology for this testing which will be overseen by a Cardiologist and/or 190 Exercise Physiologist. Again, participants will be given parking directions and a 191 map to indicate where to go for this appointment.

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Step 3: Enrollment/Randomization Visit 194 During the enrollment visit, scheduled within 2 weeks of the screening visit (Step 2), 195 patients will complete the baseline 6-minute walk test, baseline blood draw, blood 196 pressure, height, weight, complete all questionnaires (Barriers Self Efficacy, CHAMPS 197 activities questionnaire for Older Adults, Fruit &Vegetable Intake, Fat Intake, Exercise 198 Self-Efficacy, Lifestyle and Clinical Survey, San Diego Claudication Questionnaire, The 199 SF-12 Health Survey, Social Support and Exercise Survey, Supplemental questions, 200 Treatment Self-Regulation Questionnaire, VascQOL, and Walking Impairment 201 Questionnaire), and undergo randomization.

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Outcome Measures/Dependent Variables (Table 1): 204 • Primary Outcome Assessment: 6-Minute Walk Test 205 The 6-minute walk test is the most widely accepted and objective measure of 206 walking distance. In contrast to treadmill testing, it provides information on 207 patients' ability to walk in the community, thus it is a useful measure of the 208 functional outcomes of our behavioral intervention to promote home-based 209 walking. The test is conducted by placing two cones 50 feet apart in a marked 210 hallway and instructing patients to walk as many laps around the cones as 211 possible. Patients are permitted to stop walking during the test, but recording of 212 time will continue during the rest period. We will record time and distance to 213 onset of leg discomfort, rate of perceived exertion at baseline, minute 2, minute 4 214 and post-test, total distance walked (feet). In a prior study involving 64 patients 215 with PAD, the reliability coefficient for distance during 6-minute walk tests 216 performed one week apart was 0.94 with a coefficient of variation of 11.7% 2 . 217 • Secondary Outcome: Accelerometry-Measured Home-Based Walking: 218 For patients who have met eligibility criteria, we will distribute an Actigraph 219 accelerometer MODEL GT3XE (ActiGraph, Pensacola, FL) to objectively 220 measure total physical activity and bouts of home-based walking. It uses an 221 internal vertical plane accelerometer to measure both movement and intensity. 222 The analog acceleration signal is processed by an analog-to-digital converter, 223 producing a unit-less "count" value proportional to the number of movements 224 (similar to the number of steps from a pedometer) and the velocity of those 225 movements. The user specifies the time interval over which these values will be 226 summed (10-second intervals for this study). Count values are stored in the 227 ActiGraph's internal memory and uploaded to a computer for processing. The 228 ActiGraph is lightweight, small, and worn on the waist, so it will detect whole-229 body movement and functions particularly well with walking activity. At the 230 screening visit and at months 6 and 12, we will distribute accelerometers and a 231 return envelope. Participants in all study arms will wear the ActiGraph monitor 232 for 7 days at each of these three time points. Initially distributing the 233 accelerometer at treadmill test session will allow for collection of accelerometer 234 data prior to randomization. 235 By using a custom-developed program 3 , ActiGraph data will be reduced to 236 several summary variables excluding bouts of at least 60 minutes of continuous 237 zeros indicative of times the monitor was not worn. At least three days of data 238 will be needed to be included in the data set and all days with at least 10 hours of 239 data. First, we will calculate average counts per day across all days. Second, we 240 will classify ActiGraph counts into intensity categories of sedentary, light, and 241 walking activity using individually determined ActiGraph count cutoffs based on 242 count values obtained during the baseline 6-minute walk test. Because PAD 243 patients have limited functional ability, we will not calculate a count cutoff 244 distinguishing true moderate (3-5.9 times resting metabolic rate; 3-5.9 METs) or 245 vigorous intensity physical activity (6 times resting metabolic rate; equivalent to a 246 5 mph jog). We will use individual-level cutoffs for this population since no 247 cutoffs have yet been established for older adults with limited mobility. The 248 individual cutoff approach has been supported for use in older adults and for 249 intervention research. To determine sedentary and walking intensity count 250 cutoffs, ActiGraphs will be set to record data in 10-second intervals. The cutoff 251 between sedentary and light activity will be determined by having the subject sit 252 quietly in a comfortable chair; the cutoff between light and walking intensity 253 activity will be determined from the average count values obtained by asking the 254 participant to walk for 3 minutes at their normal walking pace. The start and finish 255 time will be recorded. We will use the shorter time interval (10 seconds vs. 1 256 minute) due to the intermittent nature of PAD patients' walking. Times when the 257 patient is resting will not be used for calculation of count cutoffs. 258 • Quality of Life (QOL): The SF-12 and VascQOL questionnaires: 259 The SF-12 is a shorter version of the SF-36 and has been validated in older AAs. 260 It assesses general QOL. The VascQOL is disease specific and assess how 261 each person has been affected by the poor circulation in their legs over the past 262 two weeks. 263 • Supplemental Questions: 264 There are six additional questions that ask about decision making behavior, 265 unfairness, and the participant's insight on his/her standing in the community 266 (i.e., self-perception). Potential Mediators 280 • Self-Efficacy for Exercise: Barriers Self-Efficacy and Exercise Self-Efficacy: 281 We will utilize two measures to assess barriers to self-efficacy. The Barriers Self-282 Efficacy Scale, a 13-item measure, was designed to assess participants' 283 perceived capabilities to exercise three times per week over the next 2 months 284 while facing common barriers. Participants indicate their degree of confidence for 285 internal consistency of this measure is also high (α =0.92). The confidence 290 scores from the above measures will be summed and divided by the total number 291 of items giving a possible range of 0-100%. These two measures will be 292 combined to provide a summary score of overall exercise efficacy. 293 • Social Support: 294 The Social Support for Exercise Scale 4 contains 13 items describing a supportive 295 behavior and assessing the extent to which friends and family demonstrate this 296 support using a 5-point Likert scale (ranging from 1=none to 5=very often). This 297 scale then is used to derive two subscales, one describing family support and 298 one describing support from friends. This scale has been shown to demonstrate 299 sufficient construct validity and reliability 4 . Criterion-related validity has also been 300 reported in that social support for PA has been significantly associated with 301 actual PA (r =.23 to r =.46) 4 . 302 • Intrinsic-Extrinsic Motivation: 303 Intrinsic motivation is a key concept in our theoretical model and it will be 304 assessed with the Treatment Self-Regulation Questionnaire (TSRQ complete. Leg symptom subtypes will be analyzed as potential 328 moderators.

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o We will determine atherosclerotic risk factor control. For smoking habits, 330 we will ascertain current and past smoking habits. For glucose and lipid 331 control, we will complete blood draws for glycosylated hemoglobin and 332 lipid profiles (fasting). For blood pressure control, we will obtain three 333 serial blood pressure measurements, each separated by 2 minutes. The 334 results will be averaged. 335 o We will use the Community Healthy Activities Model Program for Seniors 336 (CHAMPS) Questionnaire to assess physical activity. We will administer 337 the 42-item questionnaire, designed for use among older persons, at 338 baseline, 6, and 12 months to all three groups to assess frequency and 339 duration of various physical activities typically undertaken by adults. 340 Among a sample with a mean age of 74 years, 6-month stability of this 341 instrument ranged from 0.58-0.67, using intraclass correlation 342 coefficients. All measures were sensitive to change with a P < 0.01. This 343 questionnaire was validated for use in African Americans. 344 • Fruit & Vegetable Intake and Fat Intake: 345 These two intakes will be used to assess dietary habits. The Fruit & Vegetable 346 Intake asks participants to recall their servings of specific fruits and vegetables 347 over the last week. The Fat Intake asks participants to recall specific foods that 348 they have eaten over the past month. Both intakes will be assessed at baseline, 349 6-months, and 12-months. 350 • Walking Impairment Questionnaire (WIQ): 351 The WIQ is a disease-specific questionnaire validated in patients with PAD. It 352 consists of four subcategories: pain, distance, walking speed, and stair climbing.

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WIQ will be assessed at baseline, 6-months, and 12-months. 354 • Stage of Change: 355 The Patient-Centered Assessment and Counseling for Exercise (PACE) score 356 will be used to identify a participant's stage of readiness for exercise. To obtain a 357 PACE score, a participant chooses one of eight graded statements that best 358 describe his/her current level of and interest in physical activity. This score 359 determines the "Stage of Change" that they are in 5 . 360 361 PACE and MI interventions: 362 Both interventions will consist of nine sessions that occur between randomization and 363 the 6-month follow-up. There will be four in-person and five telephone sessions with a 364 trained counselor. The MI and PACE sessions will be audio-taped and they may also be 365 videotaped for fidelity purposes. In addition to the baseline, 6-month, and 12-month assessments, the control arm will 404 only receive phone calls at months three and nine. The purpose of these phone calls is 405 to get a general health update and to thank them for their participation in the study.

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Follow-up: 408 We will assess all patients during in-person visits at 6-and 12 months. During the 409 follow-up in-person visits, participants will be asked to complete the 6-minute walk test, 410 a blood draw (lipid panel, A1C, and 60 ccs for stored blood), blood pressure, height, 411 weight, and all questionnaires except the Lifestyle and Clinical Survey (LCS), which is a 412 medical history questionnaire intended for use only at baseline. We will also capture 413 accelerometer data during each follow-up visit. At 6-and 12 months, we will give 414 patients the accelerometer and an envelope to mail it back to our study team. The 415 morning after the 6-and 12-month follow-up assessments, we will call the patient with a 416 reminder to wear the device. They will be called again on days 3 and 7 to answer 417 questions. ABI will be re-assessed at the 12 month follow-up.

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Inclusion Criteria 420 1. African American (determined by self-report) 421 2. Lived most of their life in the United States 422 3. Resting ABI < 0.995to assess for PAD 423 4. English speaking 424 5. Has a telephonerequired for delivery of the intervention 425 426 Exclusion Criteria 427 1. Currently walking for exercise at least 5 days per week (i.e., a PACE score ranging 428 from 5-8); the rationale is that a person who is currently walking for at least 5 days 429 per week is already sufficiently active and therefore not a member of the target 430 population for our motivational home-based walking intervention. 431 2. Prior major amputation (foot or lower leg) or critical leg ischemia (tissue loss, 432 gangrene, or ulcers) 433 3. Rest pain with ABI <0.4 and non-palpable femoral pulses without prior evaluation by 434 a vascular surgeon, given the need for evaluation for the role of more invasive 435 therapy prior to recommending walking therapy 436 4. Leg revascularization within 3 months of enrollment or plans for revascularization 437 during the study period; the rationale is that post intervention recovery and potential 438 complications are likely to limit the patient's ability to adhere to the study protocol. 439 5. Use of supplemental oxygen; the rationale for this is concern for participant safety 440 and potential limited ability to participate in the study secondary to breathing 441 difficulty. 442 6. Myocardial infarction within the preceding 3 months; the rationale for this is 443 participant safety and the potential risk for complications and/or the need for 444 supervised cardiac rehabilitation following the event. 445 7. Resting blood pressure > 200/110 mmHg; the rationale for this is participant safety, 446 as blood pressure may further increase during exercise and increase risk for a 447 cerebrovascular event or myocardial infarction. 448 8. Exercise-induced coronary ischemic symptoms, or exercise-induced ST depression 449 > 2.0 mm; the rationale for this is participant safety and the need for further cardiac 450 evaluation prior to involvement in walking therapy 6 . 451 9. Inability to walk for 2 minutes; the rationale being that people who cannot walk for 2 452 minutes would not be able to complete the necessary submaximal treadmill test, 453 which is used to screen for coronary ischemic symptoms. We will also exclude 454 anyone who can walk for 20 minutes or more during the submaximal treadmill test.

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Anyone who can complete the submaximal test would not have significant walking 456 impairment and would not get that much out of the study. Short Physical 457 Performance Battery score of 11 or higher as such persons do not have a clinically 458 significant impairment in mobility; therefore, we will exclude anyone who scores a 459 11 or higher (out of a maximum of 12 points).

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Recruitment Strategies 462 We will post flyers and brochures at local sites, including clinics, senior centers and 463 churches within Wichita. We will obtain permission from appropriate leaders prior to 464 posting or displaying any material. Letters will be sent to local physicians and church 465 and community center leaders notifying them of the study and asking for referrals. A 466 mass mailing postcard will also be sent out. In addition, we will use local newspaper and 467 radio advertisements. The study will also be advertised on the KUSM-W facebook page, 468 through a broadcast email that goes to KU faculty, students and staff, and in the 469 Jayhawk Talk Online publication. All advertisements have been developed with the KU 470 Public Affairs Office and will be submitted for IRB review.

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The study team will attend local and regional health fairs and other community events in 473 an effort to recruit participants. The ABI screening will be performed at these events.

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Retention Strategies 476 A variety of items will be given or mailed to participants to keep them informed and 477 engaged in the study. Participants and their physicians will receive letters updating them 478 on the lab results and treadmill results that are obtained as part of study procedures. 479 Participants will also receive Thank you and Birthday postcards throughout the study as 480 applicable. In addition, participants will be given study brochures and handouts with 481 PAD and study specific information and a card with important phone numbers.

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Informed Consent Process 484 Participants will call in response to advertisements or physician referrals. Verbal 485 consent will be obtained from study staff for the phone screening and for the ABI done 486 as part of mass screening events. Written consent will be obtained by study staff when 487 the participants come to the initial in-person screening. If the participant is seen in their 488 home for the ABI and SPPB, they will first sign the screening consent form and if they 489 qualify for the study, they will sign the full study consent before completing the treadmill 490 test. Participants will have an opportunity to review the consent form and ask questions 491 prior to signing. Participants will not be coerced into signing but they will be notified that 492 participation in the study cannot proceed without a signed consent form.

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Sample Size Justification 495 Sample size and power calculations used the common sample size formula for normally 496 distributed statistics with a type I error level of α (2-sided test) and type II error of β: where Δ denotes the minimal meaningful difference to detect and V denotes the 500 variance of the test statistic. For the ANCOVA analyses, V=2*σ2(1-ρ2) where σ2 is the 501 (average) variability of the 6-minute walking distance at baseline and follow-up and ρ is 502 the (average) correlation between baseline and follow-up measurements.136 The 503 estimates for the sample size required in each arm are presented in Table 2  Based on a correlation of 0.75, we will have 92% power for each of the primary 515 hypotheses with 57 patients in each arm having complete follow-up. If the correlation is 516 as low as 0.65, we will have 83% power. While the calculations above assume 517 homoscedasticity, this is for sample size and power estimation purposes. Analyses will 518 use robust variance estimation for confidence intervals and P-values. Supportive 519 analyses adjusting for potential imbalances in baseline variables between treatment 520 groups will also be considered for added precision. General feasibility for adaptation to 521 standard clinical practice will be evaluated by considering both an estimate of 522 effectiveness, taking into account the level of counseling interaction received, as well as 523 an estimate of efficacy for the planned frequency and duration of patient interaction. 524 Attrition will be a potential limitation to the interpretation and generalizability of results. 525 The planned enrollment of 204 is inflated to balance potential attrition. We expect to be 526 able to hold attrition to no more than 15%. However, if we observe a rate as high as 527 20% we will still have 91% power with a correlation of 0.75 and 80% power with a less 528 optimistic correlation of 0.65. Thus, in the event that we observe both a lower 529 correlation and 33% higher attrition than expected, this study will still have 80% power 530 to detect the outcome of interest. Extensive efforts to minimize the amount of missing 531 data are summarized in section D5. Despite our best efforts, some missing data is likely 532 to be unavoidable. If the missingness is missing completely at random, the 533 consequence will merely be lost precision. If the data are missing at random, 534 conditioned on measured covariates, then supplementary analyses adjusting for these 535 covariates will produce unbiased results. For missing data mechanisms beyond 536 measured covariates, we will examine the extent to which results may be affected.

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Multiple imputation will also be considered for missing data issues. 538 539

BENEFITS AND RISKS OF RESEARCH 540 541
Known and Anticipated Risk 542 We will use counseling strategies (i.e., stage of readiness to change approach or 543 motivational interviewing techniques) and survey data for our interventions and data 544 collection, respectively. Our counseling strategies have been used in prior studies 545 without harm to participants but there could be unforeseen anxiety that arises from 546 receipt of these strategies or with completing survey questions. We will be very 547 cognizant of participant perceptions of counseling techniques and/or survey questions in 548 an effort to attenuate any anxiety related to our study protocols. 549 550 Potential additional risks to participants: 551  Unforeseen anxiety from discovering they have atherosclerosis in one or more 552 vessels of their body.

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 Increased fatigue from the use of routine exercise. This fatigue will subside as 554 they become more accustomed to exercising.

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 Increased leg pain from the use of routine exercise. 556  Having blood drawn may lead to soreness at the site or the development of a 557 bruise. The risk from this blood draw is the same as the risk as when blood is 558 removed for routine laboratory work. 559 560 Anticipated Benefit 561 The potential benefits to subjects in either Tx2 or Tx3 are an increase on physical 562 activity and reduction of walking impairment from PAD. There are no expected benefits 563 for the control group. Plan for Monitoring and Reporting Unanticipated Problems 571 We designed the screening criteria with great care and consideration in order to exclude 572 those participants who could not safely engage in a walking study. Throughout the study 573 we will actively screen for adverse events every three months. We will also have an 574 adverse event hotline that participants can call at any time. The statistician will regularly 575 pull reports to look for patterns of adverse events. The PI will review events that require 576 more immediate attention to determine the appropriate care and reporting. A Data 577 Safety Monitoring Board (DSMB) will meet every six months. However, the frequency 578 may vary depending on participant enrollment and frequency and severity of adverse 579 events. Any adverse events will be reported to the local IRB and the DSMB 580 simultaneously. A follow-up report will be submitted to the IRB to further clarify if the 581 event has been determined related to the study by the DSMB.

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Study Withdrawal/Discontinuation Procedures 584 During the consenting process, participants will be informed that, at any time, they can 585 withdraw from the study. Confidentiality 591 The data will be entered and stored on a password-protected computer at KUSM-W, 592 secured under lock and key with access restricted to research personnel only. In 593 addition, HSC2 and government and regulatory bodies will have access, as required by 594 law.

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Privacy 597 The consent interview will be conducted in private to protect the conservation from 598 being heard by others. 599 600 All study participants will be randomly assigned a study number. This number will not 601 be associated with any identifying participant characteristics such as date of birth, social 602 security number or medical record number. Any identifying participant information and 603