Revising and Revising and Resubmitting an NIH Resubmitting an NIH

R01:R01:

Exercise Training to Reduce Exercise Training to Reduce Claudication: Arm Ergometry Claudication: Arm Ergometry

versus Treadmill Walkingversus Treadmill Walking

Diane Treat-Jacobson, PhD, RNDiane Treat-Jacobson, PhD, RNAssociate ProfessorAssociate Professor

University of Minnesota School of University of Minnesota School of NursingNursing

AcknowledgementsAcknowledgements Co-InvestigatorsCo-Investigators

Jean Wyman, PhD, RN; Professor, NursingJean Wyman, PhD, RN; Professor, Nursing Arthur S. Leon, MD, MS; Professor, KinesiologyArthur S. Leon, MD, MS; Professor, Kinesiology Patricia Painter, PhD; Associate ProfessorPatricia Painter, PhD; Associate Professor Ruth Lindquist, PhD, RN; Professor, NursingRuth Lindquist, PhD, RN; Professor, Nursing Daniel Duprez, MD, PhD; Professor, MedicineDaniel Duprez, MD, PhD; Professor, Medicine Ulf Bronas, PhD; Clinical Assistant ProfessorUlf Bronas, PhD; Clinical Assistant Professor Kay Savik, MS; StatisticianKay Savik, MS; Statistician

ConsultantsConsultants Mark Creager, MD; Professor of Medicine, Harvard Mark Creager, MD; Professor of Medicine, Harvard

Medical School, Brigham and Women’s HospitalMedical School, Brigham and Women’s Hospital Judith Regensteiner, PhD, Professor of Medicine, Judith Regensteiner, PhD, Professor of Medicine,

University of Colorado Health Sciences CenterUniversity of Colorado Health Sciences Center

Objectives

Describe randomized clinical trial Describe randomized clinical trial submitted to NHLBIsubmitted to NHLBI

Discuss content of summary Discuss content of summary statementstatement

Discuss approach to grant revisionDiscuss approach to grant revision Describe process of revising grantDescribe process of revising grant

Background and Background and SignificanceSignificance

Peripheral arterial disease (PAD) is a Peripheral arterial disease (PAD) is a progressive atherosclerotic diseaseprogressive atherosclerotic disease

Affects approximately 9 million Affects approximately 9 million AmericansAmericans

Symptoms of PAD are related to Symptoms of PAD are related to insufficient arterial blood flow, which insufficient arterial blood flow, which results in debilitating, activity-induced, results in debilitating, activity-induced, ischemic pain (claudication)ischemic pain (claudication)

Associated with major limitations in Associated with major limitations in mobility and physical functioning, and mobility and physical functioning, and decreased quality of life. decreased quality of life.

Background and Significance

Efficacy of treadmill training to Efficacy of treadmill training to improve walking distance in patients improve walking distance in patients with claudication is well establishedwith claudication is well established

Mechanisms by which exercise Mechanisms by which exercise training improves walking include both training improves walking include both local and systemic changes. However, local and systemic changes. However, the contribution of these changes has the contribution of these changes has not been fully elucidatednot been fully elucidated

What is the mechanism of What is the mechanism of improvement in walking improvement in walking

distance?distance?

Local conditioning effect – changes in Local conditioning effect – changes in muscle metabolism stimulated by muscle metabolism stimulated by exercising specific muscles affected exercising specific muscles affected by limited blood flowby limited blood flow

Systemic effect – changes in central Systemic effect – changes in central cardiovascular conditioning and/or cardiovascular conditioning and/or vascular function, leading to vascular function, leading to improved walking abilityimproved walking ability

Pathophysiological Changes with Claudication

Arterial Flow Skeletal Muscle

Oxygenation Cardiac OutputEndothelial

DysfunctionInflammationThrombogenic Activity

Health and Functional Consequences Health and Functional

Outcomes

Walking AbilityFunctional StatusQuality of LifeMood

Walking AbilityFunctional StatusQuality of LifeMood

Cardiovascular Conditioning

? Skeletal Muscle Oxygenation

Endothelial DysfunctionInflammationThrombogenic Activity

Arm Ergometry(Non-Ischemic)

Treadmill Walking(Ischemic)

? Cardiovascular Conditioning

Skeletal Muscle Oxygenation

Endothelial Dysfunction Inflammation Thrombogenic Activity

Physiological Outcomes with Aerobic

Training

Conceptual Framework

Preliminary DataPreliminary Data

The Exercise Training for Claudication StudyThe Exercise Training for Claudication Study Primary Aim: To compare the effectiveness of 12 Primary Aim: To compare the effectiveness of 12

weeks of supervised arm ergometry and treadmill weeks of supervised arm ergometry and treadmill walking exercise training, alone or in combination, walking exercise training, alone or in combination, versus “usual care” controls to improve pain free and versus “usual care” controls to improve pain free and maximal walking distance (PFWD and MWD) in maximal walking distance (PFWD and MWD) in patients with lifestyle limiting claudication. patients with lifestyle limiting claudication.

Group Baseline PFWD(Meters

)Mean (SD)

Change in

PFWD (Meters

)Baseline to 12 WeeksMean (SD)

Change in PFWD

Logarithmic

transformation

Baseline to 12 Weeks Adj. Mean

(SE)

ANCOVA

F= 3.3p=.032

Change in

PFWD (Mete

rs)Baseline to

24 Week

sMean (SD)

Change in PFWD

Logarithmic

transformation

Baseline to 24 WeeksAdj. Mean

(SE)

ANCOVA

F= 5.3p=.006

Arm-ergometr

y n=10

133.1 (64.1)

89.6 (74.0)

0.24 (0.07) p=.03 vs.

Control

139.7 (97.2

)

0.34 (0.08) p=.01 vs.

Control

Treadmilln=11

200.4 (151.4)

91.6 (148.4

)

0.14 (0.06) p=.20 vs.

Control

155.1

(180.7)

0.22 (0.07) p=.11 vs.

Control

Combination

n=12

173.6 (100.4)

61.94 (109.9

4)

0.17 (0.06) p=.11 vs.

Control

21.6

(81.3)

0.04 (0.07) p=1.00 vs.

Control

Controln=8

119.2 (62.2)

4.0 (45.4)

-0.10 (0.08)

10.9(27.4

)

-0.07 (0.09)

Planned comparisons: Bonferroni Adjustment for Multiple Comparisons

Change in Pain Free Walking Distance*

* Treat-Jacobson, Bronas, & Leon (in press)

Measurement Time Points

Baseline 12 Week* 24 Week*

Pai

n F

ree

Wal

king

Dis

tanc

e (l

og.m

eter

s)

1.9

2.0

2.1

2.2

2.3

2.4

2.5

2.6

TreadmillCombinationArm ErgometryControl

Pain Free Walking Distance

*12 and 24 week values adjusted for baseline PFWD and unsupervised exercise**p<.05 arm ergometry versus control

**

**

Group Baseline

MWD Meter

s Mean (SD)

Change in MWD MetersBaseline to 12 WeeksMean (SD)

Change in MWD Log

transformation

Baseline to 12 Weeks Adj. Mean

(SE)

ANCOVA

F=10.3p<.001

Change in

MWD MetersBaseline to

24 WeeksMean (SD)

Change in MWD Log

transformation

Baseline to 24 WeeksAdj. Mean

(SE)

ANCOVA

F= 5.7p=.004

Arm-ergometr

y

421.6 (188.

7)

182.1 (126.7

)

0.18 (0.03)

p=.002 vs.

control

240.3 (164.

1)

0.23 (0.04)

p=.01 vs.

control

Treadmill 483.3 (290.

9)

294.7 (163.5

)

0.23 (0.03)

p<.001 vs.

control

294.4 (162.

2)

0.20 (0.03)

P=.02 vs.

control

Combination

441.3 (184.

1)

217.2 (72.7)

0.22 (0.03)

p<.001 vs.

control

109.7 (159.

6)

0.12 (0.03)

P=.73 vs.

control

Control 360.8 (185.

2)

45.3 (92.7)

0.02 (0.04)

73.3 (65.6)

0.03 (0.04)

Change in Maximal Walking Distance*

Planned Comparisons: Bonferroni Adjustment for Multiple Comparisons* Treat-Jacobson, Bronas, & Leon (in press)

Measurement Time Points

Baseline 12 Week* 24 Week*

Max

imal

Wal

kin

g D

ista

nce

(lo

g/m

eter

s)

2.4

2.5

2.6

2.7

2.8

2.9

3.0

TreadmillCombination Arm ErgometryControl

Maximal Walking Maximal Walking DistanceDistance

*12 and 24 week values adjusted for baseline MWD and unsupervised exercise**p<.05 versus control (all exercise groups @ 12 weeks, arm ergometry & treadmill @ 24 weeks)

****

Specific Aim 1

Determine the relative efficacy of 12 Determine the relative efficacy of 12 weeks of supervised treadmill weeks of supervised treadmill (n=60) versus arm ergometry (n=60) versus arm ergometry exercise training (n=60) versus exercise training (n=60) versus “usual care” (controls) (n=30) in “usual care” (controls) (n=30) in persons with claudication on pain persons with claudication on pain free walking distance (PFWD) and free walking distance (PFWD) and maximal walking distance (MWD), maximal walking distance (MWD), controlling for unsupervised controlling for unsupervised exercise. exercise.

Specific Aim 2

Determine the relative effects of supervised Determine the relative effects of supervised arm ergometry or treadmill training versus arm ergometry or treadmill training versus controls on local and systemic factors controls on local and systemic factors contributing to improvement in walking contributing to improvement in walking distance, including the following:distance, including the following: 2a. Measures of endothelial function in both upper 2a. Measures of endothelial function in both upper

and lower extremities and lower extremities 2b. Systemic physiologic measures associated with 2b. Systemic physiologic measures associated with

endothelial function, inflammation, and thrombosis endothelial function, inflammation, and thrombosis 2c. Cardiovascular function2c. Cardiovascular function 2d. Calf skeletal muscle oxygen saturation2d. Calf skeletal muscle oxygen saturation 2e. Correlates of physiologic measures (a-d above) 2e. Correlates of physiologic measures (a-d above)

Specific Aims 3- 5

Determine the relative efficacy of supervised Determine the relative efficacy of supervised arm ergometry versus treadmill training arm ergometry versus treadmill training versus “usual care” on functional and health versus “usual care” on functional and health status, mood, and quality of life.status, mood, and quality of life.

Evaluate the extent to which training-induced Evaluate the extent to which training-induced improvements (a-d above) are maintained or improvements (a-d above) are maintained or improved 12 weeks following completion of a improved 12 weeks following completion of a supervised exercise program.supervised exercise program.

Evaluate the response to exercise training Evaluate the response to exercise training measured in Aims 1 through 4 above, measured in Aims 1 through 4 above, independently for women and men. independently for women and men.

Concept - MeasureConcept - Measure

Walking Distance - PFWD & MWD via graded Walking Distance - PFWD & MWD via graded treadmill testtreadmill test

Upper body fitness - Graded arm ergometry testUpper body fitness - Graded arm ergometry test Arterial Flow - Arm and leg flow-mediated Arterial Flow - Arm and leg flow-mediated

vasodilation (FMD) vasodilation (FMD) Skeletal Muscle Oxygenation - Near Infrared Skeletal Muscle Oxygenation - Near Infrared

Spectroscopy (NIRS) at rest and during exerciseSpectroscopy (NIRS) at rest and during exercise Cardiovascular Functioning - Non-invasive Cardiovascular Functioning - Non-invasive

cardiac output; oxygen consumption; BP - cardiac output; oxygen consumption; BP - during both arm and treadmill testingduring both arm and treadmill testing

Concept - Measure

Endothelial Dysfunction/injury - FMD, ADMA, von Endothelial Dysfunction/injury - FMD, ADMA, von Willebrand factor; soluble P-selectin, soluble Willebrand factor; soluble P-selectin, soluble thrombomodulinthrombomodulin

Inflammation - HS C-reactive protein, Inflammation - HS C-reactive protein, interleukin-6interleukin-6

Thrombosis - Fibrinogen, TPAThrombosis - Fibrinogen, TPA Community-based walking impairment - Walking Community-based walking impairment - Walking

Impairment QuestionnaireImpairment Questionnaire Health Status – SF-36Health Status – SF-36 PAD-Specific Quality of life - PAD Quality of Life PAD-Specific Quality of life - PAD Quality of Life

Questionnaire Questionnaire Mood - Profile of Mood States (POMS)Mood - Profile of Mood States (POMS)

Concept - MeasureConcept - Measure

Nonsupervised Physical ActivityNonsupervised Physical Activity

Physical Activity Monitoring – Physical Activity Monitoring – Accelerometer for 1 week periods during Accelerometer for 1 week periods during weeks 1, 5, 11, 23weeks 1, 5, 11, 23

Exercise records – Daily exercise records Exercise records – Daily exercise records kept for 1 week periods during weeks 1, 5, kept for 1 week periods during weeks 1, 5, 11, 2311, 23

Power Analysis/Sample sizePower Analysis/Sample size

Power Analysis was based on secondary Power Analysis was based on secondary outcome of change in flow-mediated outcome of change in flow-mediated vasodilation (FMD). vasodilation (FMD).

Major analysis a repeated measures analysis Major analysis a repeated measures analysis of covariance using a random coefficient of covariance using a random coefficient model analysis model analysis

Sample size adjusted to allow for separate Sample size adjusted to allow for separate analysis of men and womenanalysis of men and women

N= 150; arm ergometry: n=60 (30 m, 30 f); N= 150; arm ergometry: n=60 (30 m, 30 f); treadmill: n= 60 (30 m, 30 f); control n=30 treadmill: n= 60 (30 m, 30 f); control n=30 (15 m, 15 f). (15 m, 15 f).

Plan to over-sample by 10% to account for Plan to over-sample by 10% to account for dropouts (total n =165)dropouts (total n =165)

Entry CriteriaEntry Criteria

InclusionInclusion Age Age >> 18 years 18 years Resting ABI Resting ABI << 0.90 0.90

or 20% drop in or 20% drop in post-exercise ABIpost-exercise ABI

Lifestyle limitation Lifestyle limitation due to claudicationdue to claudication

Ability to complete Ability to complete study proceduresstudy procedures

ExclusionExclusion Uncontrolled hypertension Uncontrolled hypertension

or diabetesor diabetes Recent peripheral or Recent peripheral or

coronary revascularization coronary revascularization procedureprocedure

Fontaine stage 3 (rest Fontaine stage 3 (rest pain) or 4 (tissue loss)pain) or 4 (tissue loss)

Unstable heart diseaseUnstable heart disease Walking limited by factors Walking limited by factors

other than claudicationother than claudication

Study Design

Treadmill Training (n=60) 3x/week for

12 weeks

Arm Ergometry (n=60) 3x/week for

12 weeks

Control (n=30) Brief Visit 1/week

for 12 weeks

6 Week Visit (2 day)

12 Week follow-up(Monthly Phone

Calls)

12 Week follow-up(Monthly Phone

Calls)

12 Week follow-up(Monthly Phone

Calls)

12 Week Visit (2 day)

24 Week Visit (2 Day)

Ra

nd

om

iza

tio

n

Screening Period2-3 weeks

Intervention Period

12 weeks

Follow-up Period

12 weeks

Sc

ree

nin

g 1

Sc

ree

nin

g 2

Ba

se

lin

e 1

Ba

se

lin

e 2

Pre

-Sc

ree

nin

g

Measurement Time point

Screening 1

Screening 2

Baseline 1(a)

Baseline 2(b)

6 Week Visit

(a & b)

12 Week Visit

(a & b)

24 Week Visit

(a & b)

Informed Consent X

Medical History X

ABI X X X X X X

Post-Exercise ABI X

Treadmill Familiarization

X

Cardiopulmonary Treadmill

X X X X X

Skeletal Muscle Oxygen Saturation

X X X X

Blood Biomarkers X

Questionnaires X X X X

Vascular Function Studies (FMD)

X X X X

Cardiopulmonary Arm Ergometry

X X X X

Cardiac Output X X X X X

Schedule of Measurements

Exercise Training Locations

Participants have a choice of Participants have a choice of exercise training locationsexercise training locations University of Minnesota (Minneapolis)University of Minnesota (Minneapolis) Fairview Southdale (Edina)Fairview Southdale (Edina) Fairview Ridges (Burnsville)Fairview Ridges (Burnsville) United Hospital (St. Paul)United Hospital (St. Paul) Possible to add additional sites if neededPossible to add additional sites if needed

Exercise GroupsExercise Groups

Supervised 3 times/week for 12 Supervised 3 times/week for 12 weeksweeks

Sessions 70 minutes in length, 5 Sessions 70 minutes in length, 5 minutes warm-up, 60 minutes of minutes warm-up, 60 minutes of exercise, 5 minutes cool downexercise, 5 minutes cool down

Recording of exercise outside Recording of exercise outside supervised setting (weeks 1, 5, 11, supervised setting (weeks 1, 5, 11, 23)23)

Treadmill Exercise Treadmill Exercise ProgramProgram

Treadmill walking Treadmill walking Speed: 2.0 mphSpeed: 2.0 mph Intensity increased when participants can Intensity increased when participants can

exercise for 8 minutes without reaching exercise for 8 minutes without reaching moderate claudication level (rating: 3-4 out moderate claudication level (rating: 3-4 out of 5)of 5)

Grade increased by 1% increments Grade increased by 1% increments After 10% grade is reached, increase speed After 10% grade is reached, increase speed

at 0.1 MPH intervalsat 0.1 MPH intervals Time: 60 minutes including rest periodsTime: 60 minutes including rest periods

Upper Body Exercise Upper Body Exercise ProgramProgram

Arm Ergometry Arm Ergometry Watts start at one level below Watts start at one level below

maximal testmaximal test 2 minutes exercise, 2 minutes rest2 minutes exercise, 2 minutes rest Gradually increase watts, exercise-Gradually increase watts, exercise-

rest intervals throughout program as rest intervals throughout program as tolerated tolerated

Time: 60 minutes including rest Time: 60 minutes including rest periodsperiods

Control GroupControl Group

Instructed to continue ‘usual Instructed to continue ‘usual care’care’

Provided specific written Provided specific written walking instructionswalking instructions

Weekly follow-up at the U of M Weekly follow-up at the U of M sitesite

Post-Training AssessmentPost-Training Assessment

Re-assessment of all outcome Re-assessment of all outcome variables variables 6 weeks 6 weeks 12 weeks 12 weeks 24 weeks (12 weeks after 24 weeks (12 weeks after

completion of 12 week visit)completion of 12 week visit)

Statistical Analysis Plan

Appropriate descriptive statisticsAppropriate descriptive statistics Logarithmic transformation of Logarithmic transformation of

variables with skewed distributionvariables with skewed distribution Intention to treat analysisIntention to treat analysis Longitudinal data analysis using Longitudinal data analysis using

random coefficient modelsrandom coefficient models Model rate of change individually Model rate of change individually Model predictors and covariates of Model predictors and covariates of

rates of changerates of change Allows for nonlinear rates of changeAllows for nonlinear rates of change

Other Issues Addressed

Recruitment PlanRecruitment Plan Protocol AdherenceProtocol Adherence Participant BurdenParticipant Burden

R01 Submission

First submission February, 2007 (first First submission February, 2007 (first electronic submission cycle)electronic submission cycle)

Clinical and Integrative Cardiovascular Clinical and Integrative Cardiovascular Sciences Study SectionSciences Study Section

Primary Assignment Primary Assignment NHLBINHLBI

Secondary AssignmentSecondary Assignment NINRNINR NIANIA

R01 Submission

Study section review June 9, 2007Study section review June 9, 2007 Score available June 12, 2007Score available June 12, 2007

(while on vacation)(while on vacation) Priority Score 225Priority Score 225 Percentile Ranking 37.5%Percentile Ranking 37.5%

Ouch!Ouch!

Summary Statement

Primary and Secondary reviews were Primary and Secondary reviews were quite differentquite different

Primary Reviewer more negativePrimary Reviewer more negative Secondary Reviewer more positiveSecondary Reviewer more positive It took a while to appreciate the It took a while to appreciate the

positive comments of the second positive comments of the second reviewer in light of the first reviewer in light of the first reviewer’s remarksreviewer’s remarks

Summary – The good news

PI is new investigator but has sufficient PI is new investigator but has sufficient experience to be able to successfully experience to be able to successfully conduct proposed workconduct proposed work

Good publication productivityGood publication productivity Excellent supportive environmentExcellent supportive environment Important area of investigation is Important area of investigation is

proposedproposed Statistical analyses and methodologies are Statistical analyses and methodologies are

appropriateappropriate

Summary – The Bad News

Multiple methodological concerns Multiple methodological concerns with Aim 2with Aim 2 Limited data presented that studies are Limited data presented that studies are

feasiblefeasible Multiple variables proposedMultiple variables proposed Interference in blood markers by other Interference in blood markers by other

factorsfactors FMD difficult in legFMD difficult in leg Perception that work may reiterate what Perception that work may reiterate what

is already knownis already known

Reviewer #1

Major Concerns (To be changed)Major Concerns (To be changed) Aim 2 has plethora of endpoints Aim 2 has plethora of endpoints

(particularly blood markers)(particularly blood markers) Didn’t like use of NIRS for skeletal Didn’t like use of NIRS for skeletal

muscle Omuscle O2 2

Had concerns about being able to do Had concerns about being able to do FMD in the legFMD in the leg

Reviewer #1

Major Concerns (to be addressed) Major Concerns (to be addressed) Expressed concern about confounding Expressed concern about confounding

variables – smoking, diabetes, variables – smoking, diabetes, recommended stratifying by these recommended stratifying by these variablesvariables

Expand limitation sectionExpand limitation section Discuss statistical analysis plan by aimDiscuss statistical analysis plan by aim

Reviewer #1

Major Concerns (could be clarified)Major Concerns (could be clarified) Concern about testing being done at Concern about testing being done at

multiple sitesmultiple sites Stated that this work had been done beforeStated that this work had been done before Mentioned isometric hand exerciseMentioned isometric hand exercise Aims not different from pilot studyAims not different from pilot study Suggested skeletal muscle biopsies or Suggested skeletal muscle biopsies or

measurement of circulating endothelial measurement of circulating endothelial progenitor cellsprogenitor cells

Reviewer # 1 InvestigatorsInvestigators

Qualified to lead such an investigationQualified to lead such an investigation Although not an exercise physiologist, she has enlisted the Although not an exercise physiologist, she has enlisted the

help of experts in that areahelp of experts in that area EnvironmentEnvironment

““The environment and team assembled by the PI are The environment and team assembled by the PI are impressive”impressive”

Innovation Innovation Not very high, methodologies have been done before Not very high, methodologies have been done before

although in smaller samplesalthough in smaller samples NIRS innovativeNIRS innovative

Budget Budget Excessive – Many personnel/Co-InvestigatorsExcessive – Many personnel/Co-Investigators Cost for testing and equipment questionedCost for testing and equipment questioned

Reviewer #2

Significance - HighSignificance - High PAD major public health problemPAD major public health problem Exercise shown to improve function, QL, Exercise shown to improve function, QL,

and possibly co-morbid conditionsand possibly co-morbid conditions Potential negative effects of leg trainingPotential negative effects of leg training ““Large scale comprehensive trial Large scale comprehensive trial

comparing these 2 interventions needs comparing these 2 interventions needs to be done”to be done”

Reviewer #2

ApproachApproach Comprehensive approach to Comprehensive approach to

screening, pre-testing, screening, pre-testing, intervention, post-testingintervention, post-testing

Demonstrated they can conduct Demonstrated they can conduct trialtrial

Needed expertise and Needed expertise and infrastructure in placeinfrastructure in place

Reviewer #2

ApproachApproach Limitations with FMD and NIRSLimitations with FMD and NIRS Suggested instead using reactive Suggested instead using reactive

hyperemia via venous occlusion hyperemia via venous occlusion plethysmography to measure structural plethysmography to measure structural changes in the lower extremitychanges in the lower extremity

The inclusion of psychosocial data is an The inclusion of psychosocial data is an important component… and the important component… and the investigators should be commended for investigators should be commended for including itincluding it

Reviewer #2

InnovationInnovation Important question that begs for the type of trial Important question that begs for the type of trial

outlinedoutlined InvestigatorInvestigator

Clearly capable of conducting studyClearly capable of conducting study Excellent support from a variety of skilled co-Excellent support from a variety of skilled co-

investigatorsinvestigators Environment - Environment - OutstandingOutstanding BudgetBudget

Should be adjusted to reflect the likely replacement of Should be adjusted to reflect the likely replacement of FMD and NIRS with peak reactive hyperemia FMD and NIRS with peak reactive hyperemia measuresmeasures

Reviewer #2 - SummaryOverall Evaluation:

This is a proposal from a very strong young investigator backed by an outstanding team at an outstanding institution. There are no major structural problems with the application in terms of the question asked, the intervention proposed, and a number of the key outcome measures. However, this reviewer feels strongly that there are significant limitations with the FMD and NIRS approaches and that the peak calf reactive hyperemia studies suggested may be much more useful in addressing the key hypotheses and physiologic issues of interest in this application. The above comments are made in the most positive possible context and are designed to improve this application.

Other Reviewer Comments

Suggested increase sample size Suggested increase sample size based on number expected to be lost based on number expected to be lost at 24 weeks (versus only 12 weeks)at 24 weeks (versus only 12 weeks)

RevisionRevision

Specific Aim 1

Determine the relative efficacy of Determine the relative efficacy of 12 weeks of supervised treadmill 12 weeks of supervised treadmill (n=60) versus arm ergometry (n=60) versus arm ergometry exercise training (n=60) versus exercise training (n=60) versus “usual care” (controls) (n=30), and “usual care” (controls) (n=30), and 12 weeks of follow-up (24 weeks), in 12 weeks of follow-up (24 weeks), in persons with claudication on pain persons with claudication on pain free walking distance (PFWD) and free walking distance (PFWD) and maximal walking distance (MWD), maximal walking distance (MWD), adjusting for unsupervised exercise, adjusting for unsupervised exercise, smoking and diabetes statussmoking and diabetes status. .

Specific Aim 1

Combined previous Aim 1 and 4. Combined previous Aim 1 and 4. Added covariates of smoking and Added covariates of smoking and

diabetes in response to concerns diabetes in response to concerns from reviewer 1 and as a from reviewer 1 and as a compromise to the suggestion of compromise to the suggestion of stratification by these variablesstratification by these variables

Specific Aim 2

Determine the relative effects of Determine the relative effects of supervised arm ergometry or treadmill supervised arm ergometry or treadmill training versus controls on selected factors training versus controls on selected factors that contribute to improvement in walking that contribute to improvement in walking distance, including the following:distance, including the following: 2a. Resting, submaximal and peak limb blood 2a. Resting, submaximal and peak limb blood

flow (venous occlusion plethysmography). flow (venous occlusion plethysmography). 2b. Cardiovascular function (peak oxygen 2b. Cardiovascular function (peak oxygen

consumption, cardiac output, resting blood consumption, cardiac output, resting blood pressure). pressure).

2c. Correlates of physiologic measures. 2c. Correlates of physiologic measures.

Specific Aim 2

Replaced FMD and NIRS with peak Replaced FMD and NIRS with peak reactive hyperemia via venous reactive hyperemia via venous occlusion plethysmographyocclusion plethysmography Co-Investigators (Painter and Duprez) and Co-Investigators (Painter and Duprez) and

both consultants have expertise with this both consultants have expertise with this techniquetechnique

More literature on the use of this method in More literature on the use of this method in PAD, including exercise trialsPAD, including exercise trials

Removed blood markers from Aims and Removed blood markers from Aims and included a smaller number of markers included a smaller number of markers as supporting data as supporting data

Specific Aims 3- 4 Specific Aims 3- 4 (unchanged)(unchanged)

Determine the relative efficacy of Determine the relative efficacy of supervised arm ergometry versus supervised arm ergometry versus treadmill training versus “usual treadmill training versus “usual care” on functional and health care” on functional and health status, mood, and quality of life.status, mood, and quality of life.

Evaluate the response to exercise Evaluate the response to exercise training measured in Aims 1 training measured in Aims 1 through 3 above, independently through 3 above, independently for women and men. for women and men.

IntroductionIntroduction

Response to ReviewersResponse to Reviewers Specifically addressed each pointSpecifically addressed each point Reviewer #___ said X, we have done Y as Reviewer #___ said X, we have done Y as

reflected in section Zreflected in section Z Organized it by review criteriaOrganized it by review criteria Clarified misperceptions of Reviewer 1 – Single Clarified misperceptions of Reviewer 1 – Single

site testing, first time study done in PAD except site testing, first time study done in PAD except our pilot, reiterated differences from pilotour pilot, reiterated differences from pilot

Justified not stratifying by comorbidity – Justified not stratifying by comorbidity – including literature supportincluding literature support

Justified not including skeletal muscle biopsies or Justified not including skeletal muscle biopsies or measurement of circulating endothelial measurement of circulating endothelial progenitor cellsprogenitor cells

Introduction

Response to ReviewersResponse to Reviewers Added pilot data on change in markers of Added pilot data on change in markers of

endothelial injury and inflammation endothelial injury and inflammation following arm ergometry exercise following arm ergometry exercise

Adjusted statistical analysis plan by AimAdjusted statistical analysis plan by Aim Provided table of detectable differences Provided table of detectable differences

including all outcome variablesincluding all outcome variables Clarified budget justificationClarified budget justification Emphasized innovation including expanded Emphasized innovation including expanded

support from the literaturesupport from the literature Expanded limitation sectionExpanded limitation section

Resubmission

Resubmitted November, 2007Resubmitted November, 2007 Study Section review February 2008Study Section review February 2008

Priority Score 137Priority Score 137Percentile ranking 6.8%Percentile ranking 6.8%

Approved for funding June 2008Approved for funding June 2008Funded September 2008Funded September 2008