Prevention of Recurrent FootUlcers With Plantar PressurendashBased In-Shoe Orthoses TheCareFUL Prevention MulticenterRandomized Controlled TrialDOI 102337dc13-2956

OBJECTIVE

To assess the efficacy of in-shoe orthoses designed based on shape and barefootplantar pressure in reducing the incidence of submetatarsal head plantar ulcersin people with diabetes peripheral neuropathy and a history of similar priorulceration

RESEARCH DESIGN AND METHODS

Single-blinded multicenter randomized controlled trial with subjects randomizedtowear shape- and pressure-based orthoses (experimental n = 66) or standard-of-care A5513 orthoses (control n = 64) Patients were followed for 15 monthsuntil a study end point (forefoot plantar ulcer or nonulcerative plantar forefootlesion) or to study termination Proportional hazards regression was used foranalysis

RESULTS

There was a trend in the composite primary end point (both ulcers and nonulcer-ative lesions) across the full follow-up period (P = 013) in favor of the experimen-tal orthoses This trend was due to a marked difference in ulcer occurrence (P =0007) but no difference in the rate of nonulcerative lesions (P = 076) At 180 daysthe ulcer prevention effect of the experimental orthoses was already significant(P = 0003) when compared with control and the benefit of the experimentalorthoses with respect to the composite end point was also significant (P =0042) The hazard ratio was 34 (95 CI 13ndash87) for the occurrence of a sub-metatarsal head plantar ulcer in the control compared with experimental armover the duration of the study

CONCLUSIONS

We conclude that shape- and barefoot plantar pressurendashbased orthoses weremore effective in reducing submetatarsal head plantar ulcer recurrencethan current standard-of-care orthoses but they did not significantly reduce non-ulcerative lesions

1Department of BioBehavioral Health PennsylvaniaState University University Park PA2Department of Medicine Pennsylvania StateUniversity State College PA3Mount Nittany Health System State College PA4DIApedia LLC State College PA5DepartmentofPublicHealthSciences PennsylvaniaState University Hershey PA6Department of Orthopaedics and SportsMedicineUniversity of Washington Seattle WA

Corresponding author Peter R Cavanagh cavanaghuwashingtonedu

Received 17 December 2013 and accepted 13March 2014

Clinical trial reg noNCT00803608 clinicaltrialsgov

This article contains Supplementary Data onlineat httpcarediabetesjournalsorglookupsuppldoi102337dc13-2956-DC1

copy 2014 by the American Diabetes AssociationSee httpcreativecommonsorglicensesby-nc-nd30 for details

Jan S Ulbrecht1234 Timothy Hurley4

David T Mauger5 and

Peter R Cavanagh46

Diabetes Care 1

PATH

OPHYSIO

LOGYC

OMPLIC

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Diabetes Care Publish Ahead of Print published online April 23 2014

It has long been recognized that a footulcer is a critical step in the causal path-way for most amputations in diabetes(1) and such ulcers result in significantmorbidity and cost even when they donot lead to an amputation (2ndash4) Afteran initial foot ulcer the risk of reulcera-tion is extraordinarily high (5ndash7) insome studies 80 after 3 years (8)Approximately 40 (14ndash78) of diabeticfoot ulcers are located on the plan-tar surface related to metatarsal heads(MTHs) (9ndash13) where plantar pressureis generally highest (14) Thus such le-sions are the result of the repetitiveforces of weight bearing in patientswhose gait is unmodified by sensoryfeedback (15) This implies that thera-peutic footwear targeted to preventplantar ulceration should maximally off-load areas of high plantar pressure Thusthe variable results of studies exploringthe ulcer prevention efficacy of diabeticfootwear are likely to be at least partlydue to the fact that efficacy of the foot-wear used in terms of plantar offload-ing is usually neither defined nor tested(16) To be eligible in the US for Medi-care coverage custom in-shoe orthosesprovided (the footwear component pri-marily responsible for plantar offloading)must be custom molded to the shape ofthe patientrsquos foot but beyond that thespecifications are only generic address-ing the hardness and thickness of mate-rials that are used (Healthcare CommonProcedure Coding System [HCPCS] codeA5513)Wehave previously demonstrated that

shape- and pressure-based orthoses pro-vide superior MTH offloading comparedwith conventional A5513 diabetic ortho-ses (17) In this present Care For ULcer(CareFUL) Prevention trial we testedthe hypothesis that these same orthosesmanufactured on the basis of both bare-foot plantar pressure and foot shape aresuperior in preventing recurrence of plan-tar injury in neuropathic patients with arecently healed MTH-related plantar ulcercompared with standard-of-care orthosesmanufactured on the basis of shape andclinical information alone

RESEARCH DESIGN AND METHODS

Study SettingThis study took place at 11 outpat-ient clinic sites specializing in diabeticfoot care across the US (two each inPennsylvania Illinois California and

Arizona and one each in Ohio Texasand Colorado) and included academicmedical centers Veterans Administra-tion clinics and private practice podia-try clinics (Supplementary Appendix 1)All site principal investigators (PIs) wereclinicians with significant experiencemanaging diabetes-related foot problemsand had prior experience conductingclinical trials

Study ParticipantsMost subjects were patients at the coop-erating clinics and were recruited underinstitutional review board (IRB) approvalLocal PIs considered consecutive patientswith recently healed ulcers for inclusionin the study at each clinic site so thatsubjects who progressed to formalscreening were already highly likely tomeet the inclusion criteria which are pre-sented in full in Supplementary Appendix2 In brief inclusion criteria were as fol-lows men and women$18 years of agewith diabetes and loss of protective sen-sation (inability to feel the 10-g monofil-ament at one or more sites [18]) at leastone recently healed (1 week but 4months) plantar MTH-related foot ulcerpeak barefoot plantar pressure in thearea of this previous ulcer (the ldquoindex ul-cerrdquo) 450 kPa community ambulatorno current ulcer below the malleoli par-tial foot amputation of no greater thantwo MTHs or rays per foot (no limit ontoe amputations) no ankle-foot orthosisno existing footwear intervention morecomplex than would be available throughthe study footwear and orthotic options(eg no rigid outsole custom moldedshoes) and ability to complywith the pro-tocol All study questionnaires were avail-able in English or Spanish Peak barefootplantar pressures were measured using aNovel EMEDD platformwith a spatial res-olution of four sensors per cm2 and asampling frequency of 50 Hz using theaverage of five trials and a first walkingstep protocol (17)

Study Design and RandomizationEligible subjects were randomized in a3111 ratio (experimental orthosiscontrol orthosis 1control orthosis 2control orthosis 3 see below) Random-ization was stratified by site and sexBlocked randomization (block size 6)was used within strata The randomiza-tion tables were developed by one ofthe investigators (DTM) who was not

directly involved in managing the trialRandomization assignment was givenby the coordinating center to eachsite for each subject after eligibilitywas confirmed The study PI (JSU)study statistician (DTM) patientsand adjudicators were blinded as tothe assignment of patients to treat-ment groups

After randomization visit two for dis-pensing of footwear occurred at 79 and78 weeks in the experimental and con-trol arms respectively During this timethe protocol recommended that sub-jects remain in their healing device orin a removable cast walker providedthrough the study Subsequent visitswere the same for all footwear condi-tions and were timed to facilitate fre-quent assessment potential footwearmodification and subject educationparticularly during the break-in periodThe break-in process was formalizedStarting with dispensing of footwear(time 0) visits occurred at +1 week+3 weeks +6 weeks and then every3 months for another 15 months for apotential total follow-up time in footwearof 165 months The 15-month follow-uptime was selected based on experiencefrom other published studies (19) Sub-jects were followed to primary endpoint their volitional withdrawal or ter-mination of the study

The study was registered at httpwwwclinicaltrialsgov (NCT00803608)The overall study was reviewed and ap-proved by the Essex IRB (121 MainStreet Lebanon NJ 08833) and eachstudy site was also reviewed and ap-proved either by Essex or by a site-specific IRB

Orthoses and FootwearFor all orthoses (control and experimen-tal) foot shapewas obtained using foamboxes which were digitally scanned formanufacture of the experimental ortho-ses and sent to the manufacturer of thecontrol insoles

Manufacture of the experimental or-thoses has been previously described(17) They are initially designed to be sim-ilar to a ldquoshape onlyrdquo insole and thenmodified using a computer-aided designprocess according to defined algorithms(17) based on the peak barefoot plantarpressure distribution contours The or-thoses are then milled from a block ofethylene vinyl acetate foam (Shore A 35

2 Footwear for Diabetic Foot Ulcer Prevention Diabetes Care

durometer) using a computer-aidedmanufacturing process A laminatedfabric-PPT (polyurethane foam) top coveris added and the orthoses are hand fin-ished and shipped back to the clinical sitefor dispensing For this study the designalgorithm focused on offloading the sub-metatarsal head regionWe chose to include standard ortho-

ses from three different manufacturersin the control arm of the study in orderto make the results more generalizableHowever the studywas not powered forcomparisons of the individual control or-thoses The three manufacturers wererecognizable names in the field that rou-tinely provide Medicare-reimbursed re-motely manufactured diabetic in-shoeorthoses on the basis of foot shape andclinical information (HCPCS code A5513)The standard order form for each manu-facturer was used and the site PIs wereencouraged to request additional modi-fications such as metatarsal pads barsreliefs etc as they would do in theirclinical practiceIn all cases subjects received three

pairs of identical orthoses to be rotatedwhile using the primary study footwearaccording to a written rotation protocolchanging the numbered orthoses in aset rotation every month Subjectswere offered one of two footwear mod-els manufactured by PWMinor (BataviaNY) regardless of study group assign-ment (Performance Walker and LeisureTime) The experimental insoles re-quired more depth and thus the DX2specification was used for experimentalsubjects whereas the Extra Depth spec-ification was used for the control sub-jects Subjects in all groups were alsogiven a pair of Pedor Classic (MariettaGA) shoes with 95-mm flat trilaminateorthoses and no customization for occa-sional steps at home However theywere asked to use the primary footwearfor the majority of their indoor and out-door ambulation Subjects could useprotective overboots (eg Neos Over-shoe) in inclement weather conditionsThe orthoses and shoes could be ad-

justed by the local site staff for fit at anypoint during the trial but they could notbe modified to alter the plantar offload-ing properties Modifications such astrimming of orthoses stretching ofshoes addition of tongue pads and re-pairs were permitted whereas additionof metatarsal pads and orthotic reliefs

(after the initial prescription whichcould include these modifications) orrocker outsoles were not permitted Incases where the site PI or the subjectwas concerned about the safety of con-tinued use of the study footwear andwhen permitted modifications couldnot alleviate such concerns subjects dis-continued use of study footwear Anysubject who discontinued use of thestudy footwear for any reason for 45days was excluded from further foot-wear use and was deemed to have dis-continued study footwear permanentlybut followed where possible to permitan intent-to-treat analysis Shoes andor orthoses could be replaced usingprior data stored by the manufacturersif either were showing excessive wear inthe opinion of the PI or of the subject

Education and MotivationStudy coordinators discussed self-carebehavior with all patients regardless ofgroup assignment at each visit with aspecial focus onwearing the study shoesfor all steps taken and on examining thefeet daily to note and report problemsStudy coordinators used worksheets toencourage adherence and also usednonthreatening open-ended questionsin their conversationswith study subjectsAn educational brochure was given topatients as was a door hanger to remindsubjects daily of what they should bedoing (Supplementary Appendices 3and 4)

End Point and Descriptive MeasuresThe primary end point for the study waseither an ulcer or nonulcerative lesioninvolving the plantar surface and associ-ated with an MTH High-resolution stan-dard view digital photographs of thefeet and footwear were obtained at allstudy visits The foot photographs werereviewed initially by one of the investi-gators blinded to group assignmentand a suspected ulcer or nonulcerativeplantar lesion below the malleoli wasreferred to a panel of three blinded (asto group assignment) adjudicators allexperts in the field Photographs werereviewed in the context of the full photo-graphic series over time Lesions werejudged as absentnonulcerative lesionulcer involvingnot involving the plan-tar surface (defined as involving theweight-bearing surface of the foot)and related to MTHnot related to

MTH Adjudicators did not confer witheach other or with the study staff andthe majority opinion was taken as thefinal judgment Ulcers were judged tobe present if the integrity of both theepidermis and dermis was broken Anonulcerative lesion (20) was definedfor this study as hemorrhage into callus(all but one of such lesions adjudicated)or redness at a site of bony prominencepersisting 20 min after removalof footwear and rest based on repeatphotographs

In contrast to previous studies we in-cluded nonulcerative plantar lesions aspart of the composite primary end pointbecause we hypothesized that these le-sions would also be prevented by theexperimental footwear and becausewe felt it to be unethical to continuesubjects in footwear that ldquoallowedrdquosuch lesions to develop Safety endpoints tracked in the study includedskin injury below the malleoli not qual-ifying as primary end point as well asself-reported falls and fear of falling(21) and falls reported by sites as ad-verse events

Information obtained at the screen-ing visit included demographic detailsinformation needed for inclusionexclu-sion and for prescription of orthoses andfootwear as well as ankle-brachial index(ABI) (values absent due to noncom-pressible vessels were treated as miss-ing data) standardized foot exam fordeformity (in the analyses the defor-mity index used was for the foot withthe primary end point or right footwhen no end point occurred) (Supple-mentary Appendix 5) and baselinequestionnaires assessing neuropathy-specific quality of life (22) (Supplemen-tary Appendix 6) foot self-care (23)(Supplementary Appendix 7) and fallsand fear of falls (21) (SupplementaryAppendix 8) These three question-naires were also administered at eachfollow-up visit as was a questionnaireaddressing subject satisfaction withfootwear and footwear use (Supple-mentary Appendix 9)

Data Management and StatisticalAnalysesEach site entered study data from papersource documents into a centralized datamanagement system maintained andmanaged by the Department of PublicHealth Sciences College of Medicine

carediabetesjournalsorg Ulbrecht and Associates 3

Pennsylvania State University Data werevalidated by the coordinating centeragainst the primary source documentsFor the primary analyses Kaplan-

Meier survival curves were constructedfor graphical displays of the time-to-event outcomes Proportional hazardsregression analyses were applied totest for statistical significance of thetreatment effect Separate analyseswere performed for the composite out-come and for each of the two com-ponents time to ulcer and time tononulcerative lesionSecondary analyses using propor-

tional hazard regression examined asso-ciations between primary end pointsand various patient characteristics A lin-ear mixed-effects model was used foranalysis of patient-reported outcomesmeasured across time All analyses wereperformed using the intent-to-treat para-digm with SAS version 92 (SAS IncCary NC)The target sample size was 286 ran-

domized patients calculated to provide80 statistical power for a two-sided005 significance level test allowing for15 withdrawals to detect a 50 re-duction in the rate of reulceration Weanticipated a 15-month ulcer recurrencerate of 30 in the control footweargroup based on estimates from the lit-erature (19) and 15 in the experimen-tal footwear group based on a clinicallymeaningful risk reduction Because re-cruitment was slower than anticipatedour funder (National Institute of Diabe-tes and Digestive and Kidney Diseases[NIDDK]) requested an unplanned in-terim analysis and based upon this as-sessment we terminated recruitmentand follow-up with a final sample sizeof 150 subjects randomized The trialwas ended because to achieve a statis-tically significant effect with respect tothe primary composite end point (MTH-related plantar ulcer or nonulcerativelesion) would likely have requiredmany more subjects and a significant ef-fect in terms of ulcer prevention wasalready apparent

RESULTS

In all analyses the effect of study site onoutcomes was examined and there wereno significant effects Similarly no differ-ences were noted between the three con-trol subgroups Therefore in all subsequentanalyses the results are presented across

the full trial comparing the experimentalgroup and the control group as a whole

Study ParticipantsThe flow of subjects through the variousphases of the study is shown in theCONSORT diagram (24) in Fig 1 Twentypatients did not receive the allocatedintervention (13 experimental and 7control) This reflects clinical realitywhere several weeks often elapse be-tween footwear and orthoses beingordered and dispensed because ofmanufacturing and shipping timesSuch was the case in the current studyDuring this time events including clini-cal events can preclude footwear beingdispensed at all In the experimentalarm 7 of the 13 subjects developednew ulcers at various sites below themalleoli and therefore no longer met in-clusion criteria in the control arm thisnumber was 3 of 7 In the experimentalarm footwear could not be made to fitor was otherwise deemed unsuitable infour patients in the control arm thisnumber was two There were no statis-tically significant differences in terms ofthe baseline characteristics (see Table 1)between randomized subjects receivingfootwear and not receiving footwearexcept that those not receiving foot-wear reported higher scores for avoid-ing foot-damaging behaviors (096 vs090 P = 003)

At baseline the mean ABI was higherin the control group (P = 002) andsubjects entering the control groupshowed a trend toward higher scoreson avoiding foot-damaging behaviors(P = 007) both these biases would favorbetter outcomes in the control groupThe sample as a whole was typical ofdiabetic neuropathic patients being pre-dominantlymale in latemiddle age andobese The group was ethnically and ra-cially diverse

FootwearIn the control arm metatarsal pads orbars were provided in 59 of cases andmetatarsal reliefs (removal of materialunder anMTH) in 33 based on the opin-ionwishes of the prescribing clinician Bydesign all experimental orthoses hadpatient-specificmetatarsal bars and reliefs(17) Nine experimental and five controlsubjects received replacementsupple-mental footwear in an average of 277days after the original footwear was

dispensed (237 days experimental and351 days control)

Primary and Secondary End PointsAs shown in Fig 2A there is a clear trendtoward a difference in the compositeprimary end point (ulcers or nonulcera-tive lesions) across the full follow-up pe-riod (P = 013) This trend is due to amarked difference in ulcer occurrence(P = 0007 greater in control) (Fig 2B)whereas there is no difference in therate of nonulcerative lesions (P = 076)(Fig 2C) Examination of the Kaplan-Meier curves suggests that most ofthe benefit accrues over the first fewmonths after which the event rates ap-pear to be parallel Thus at 180 days theulcer prevention effect of the experi-mental condition is already significant(P = 0003) when compared with the con-trol condition at this point the benefit ofthe experimental condition with re-spect to the composite end point isalso significant (P = 0042)

The P values at 1 year the point atwhich footwear is usually replacedwere P = 0073 and P = 00041 for thecomposite and ulcer end points respec-tively Across the full study a primaryend point occurred in 379 (25 of 66)of subjects in the experimental arm (ul-cers in 91 6 of 66) and in 453 (29 of64) of subjects in the control group (ul-cers in 250 16 of 64) The hazard ratiowas 34 (95 CI 13ndash87) for the occur-rence of an ulcer in the control footwearcompared with the experimental condi-tion over the duration of the study

None of the baseline characteristicsexcept barefoot plantar pressure pre-dicted outcomes composite or compo-nent in either arm Higher end pointfoot-specific (or right if no end point)forefoot peak plantar barefoot pressurewas associated with higher risk of endpoint lesions Thus the peak barefootplantar pressure was on average 11311042 and 984 kPa in feet that devel-oped ulcers nonulcerative lesions andno end point respectively (P = 004) Ineach case the barefoot plantar pres-sures trended higher in the experimen-tal compared with control groups (1170vs 1116 kPa for ulcers and 1071 vs999 kPa for nonulcerative lesions P =03)

There were no changes in the re-ported quality of life fear of fallingand satisfaction with footwear over

4 Footwear for Diabetic Foot Ulcer Prevention Diabetes Care

the duration of the study All subjectsreported better average foot self-carehabits after being instructed (P 001baseline vs follow-up) No differencesbetween study arms were apparent forthese four measures over the follow-upperiod and there were no statisticallysignificant associations between any ofthese measures and outcomes Mostend point lesions occurred in the sameforefoot as the index ulcer (49 of 54 forthe composite end point 19 of 22 forulcers) There were no significant dif-ferences between groups in the occur-rence of adverse events other thanprimary end points (see SupplementaryAppendix 10)

CONCLUSIONS

The findings of the current study indi-cate that patient-specific orthoses man-ufactured on the basis of foot shape andbarefoot plantar pressure are superiorto orthoses manufactured only on thebasis of foot shape and clinical insight

Specifically the hazard ratio was 34(95 CI 13ndash87) for the occurrence ofan ulcer in the control footwear com-pared with the experimental conditionover the duration of the study This ob-servation extends the previous findingthat such orthoses are superior in off-loading the forefoot (17)

There was also a clear trend towardthe experimental condition preventingthe composite end point of skin ulcerand nonulcerative lesion (P = 004 P =007 and P = 013 at the three analysistime points) However it is also appar-ent that this trend was due to the ulcer-prevention effect of the experimentalorthoses The hypothesis that the exper-imental condition was different fromthe control condition regarding the fre-quency of nonulcerative lesions wastherefore rejected

Onepossible explanation for the lack ofdifference in the occurrence of nonulcer-ative lesions between the two groups isthat some anatomical locations that

would develop nonulcerative lesions incontrol footwear may escape damage al-together in the experimental footwearFurthermore some locations that wouldulcerate in the control condition may re-sult in nonulcerative lesions in experi-mental footwear This hypothesis issupported by the observed trend differ-ences in plantar pressure where endpoints tended to occur in feet with higherforefoot barefoot pressures in the exper-imental group than in the control Also inthis study as in others (15) occurrence ofend point lesions was associated withhigher forefoot barefoot plantar pressureregardless of study arm

Nonulcerative skin lesions particu-larly hemorrhage into callus which isthe most common lesion are an estab-lished risk factor for ulceration if left un-treated (5) However treatment toprevent a full ulcer is usual and mightinclude debridement of callus a furthermodification to or change of footwearor a change in patient behavior to

Figure 1mdashCONSORT diagram

carediabetesjournalsorg Ulbrecht and Associates 5

the duration of the study All subjectsreported better average foot self-carehabits after being instructed (P 001baseline vs follow-up) No differencesbetween study arms were apparent forthese four measures over the follow-upperiod and there were no statisticallysignificant associations between any ofthese measures and outcomes Mostend point lesions occurred in the sameforefoot as the index ulcer (49 of 54 forthe composite end point 19 of 22 forulcers) There were no significant dif-ferences between groups in the occur-rence of adverse events other thanprimary end points (see SupplementaryAppendix 10)

CONCLUSIONS

The findings of the current study indi-cate that patient-specific orthoses man-ufactured on the basis of foot shape andbarefoot plantar pressure are superiorto orthoses manufactured only on thebasis of foot shape and clinical insight

Specifically the hazard ratio was 34(95 CI 13ndash87) for the occurrence ofan ulcer in the control footwear com-pared with the experimental conditionover the duration of the study This ob-servation extends the previous findingthat such orthoses are superior in off-loading the forefoot (17)

There was also a clear trend towardthe experimental condition preventingthe composite end point of skin ulcerand nonulcerative lesion (P = 004 P =007 and P = 013 at the three analysistime points) However it is also appar-ent that this trend was due to the ulcer-prevention effect of the experimentalorthoses The hypothesis that the exper-imental condition was different fromthe control condition regarding the fre-quency of nonulcerative lesions wastherefore rejected

Onepossible explanation for the lack ofdifference in the occurrence of nonulcer-ative lesions between the two groups isthat some anatomical locations that

would develop nonulcerative lesions incontrol footwear may escape damage al-together in the experimental footwearFurthermore some locations that wouldulcerate in the control condition may re-sult in nonulcerative lesions in experi-mental footwear This hypothesis issupported by the observed trend differ-ences in plantar pressure where endpoints tended to occur in feet with higherforefoot barefoot pressures in the exper-imental group than in the control Also inthis study as in others (15) occurrence ofend point lesions was associated withhigher forefoot barefoot plantar pressureregardless of study arm

Nonulcerative skin lesions particu-larly hemorrhage into callus which isthe most common lesion are an estab-lished risk factor for ulceration if left un-treated (5) However treatment toprevent a full ulcer is usual and mightinclude debridement of callus a furthermodification to or change of footwearor a change in patient behavior to

Figure 1mdashCONSORT diagram

carediabetesjournalsorg Ulbrecht and Associates 5

more consistently comply with footwearuse use of a pedometer to manageactivity etcThe high rate of ulcer occurrence dur-

ing the first weeks of use of the controlinsoles is consistent with the clinical ob-servation that this is a particularly high-risk time It also indicates the relativeinadequacy of the control orthoses forulcer prevention The overall ulcer ratesin this study were similar to those seenin other intervention studies with high-risk patients (eg 1920)Because subjects in the experimental

arm received double-extra depth ratherthan just extra depth shoes it is plausiblethat this difference in the shoes somehow

contributed to the positive findings in thestudy Similarly since footwear use wasnot measured it is plausible that differ-ences in footwear use between experi-mental and control subjects contributedto the observed effects However wethink it likely that this effect would favorthe control condition since the double-extra depth shoes were larger and possi-bly less acceptable to the subjects

Most of the benefit apparent fromthe experimental treatment had alreadybeen achieved after6months of wearAfter that the survival curves are moreor less parallel and it therefore appearsthat footwear-related lesions occur rel-atively early after footwear is dispensed

It is possible that lesions occurring afterthe initial few months have less to dowith footwear design but rather maybe a consequence of variable activitypatterns noncompliancewith footwearetc This finding is in contrast to someother studies where the curves repre-senting the effect of nonfootwearinterventions continue to divergethroughout follow-up (19) Based onour data it may be sufficient to conductfuture footwear intervention trials for6 months or perhaps a maximum of1 year when shoes and orthoses are cus-tomarily replaced

We intentionally did not compare ef-ficacy of the pressure- and shape-basedorthoses to efficacy of custom orthosesmanufactured by hand by a skilled or-thotist or pedorthist Examination ofthe efficacy of remotely produced pres-sure-based orthoses in comparison withsuch handcrafted orthoses would be ofinterest since themanufacturing cost ofthe latter is much higher

Taken together with the recent stud-ies from the Netherlands (2025) ourdata offer some clarification of the pre-viously uncertain (1625) foundation forthe effectiveness of diabetic footwearTo increase the probability of ulcer pre-vention therapeutic footwear mustdemonstrably reduce plantar pressureat defined high-risk locations and thepatient must wear their footwearconsistently

The present findings are limited to ul-cers under the MTHs since this was thescope of the current design algorithmand the site of prior ulcers in this sampleFuture studies should examine other re-gions of the foot where similar relation-ships between plantar pressure reductionand risk reduction may be expected(1620) In addition a future study quan-titatively examining the degradation inpressure relief of various orthosesas a function of time would inform guide-lines for replacementreimbursementAlthough a definitive statement willrequire a formal cost-benefit analysisthe huge costs associatedwith foot ulcersand subsequent amputation in diabeticpatients (2ndash4) (estimated to be $107 bil-lion in 2001) (4) suggest that clinical useof the orthoses tested in this study wouldresult in significant cost savings to thehealth care system

In summary this study demonstratesthat orthoses individually designed and

Table 1mdashBaseline demographic and other characteristics of subjects whoreceived footwear

Characteristic Experimental group Control group

Number of subjects 66 64

Number of male subjects 50 (758) 52 (813)

Age in years (range) 605 6 101 (33ndash83) 585 6 107 (35ndash88)

BMI (kgm2) 323 6 71 314 6 55

Smoking 6 (91) 12 (188)

EthnicityHispanic or Latino 21 (318) 20 (302)

RaceWhitedagger 55 (833) 51 (797)African Americandagger 10 (152) 11 (172)Otherdagger 1 (15) 2 (31)

SocioeconomicAt least high school graduate 49 (742) 52 (823)Graduated college 12 (182) 18 (281)Not living alone 50 (758) 47 (734)

ABIDagger 105 6 016 113 6 018

Index ulcer locationsectMTH 1 36 (545) 29 (453)MTH 2 13 (197) 10 (156)MTH 3 2 (30) 11 (172)MTH 4 5 (76) 8 (125)MTH 5 13 (197) 11 (172)

Barefoot peak plantar pressure at priorindex ulcer site (kPa) 946 6 266 967 6 233

Barefoot peak plantar pressure atany site in either foot (kPa) 1109 6 173 1085 6 191

Prior minor amputation|| 21 (318) 24 (375)

Foot deformity indexpara 284 6 146 289 6 173

NeuroQOLPhysical symptoms 156 6 085 138 6 087Psychological symptoms 157 6 113 164 6 116

Foot self-carePreventive 066 6 021 068 6 020Avoid damaging 088 6 014 092 6 012

FallsNumber recalling a fall last year 28 (424) 34 (531)Number who worry about falling () 471 6 312 458 6 339

NeuroQOL neuropathy-specific quality of life Mean 6 SD daggerSome selected more than onerace DaggerAverage of all legs sectSome had more than one index ulcer ||See exclusion criteria paraScale0ndash100 Scale 0ndash4 0 = no symptoms Scale 0ndash1 1 = best behavior

6 Footwear for Diabetic Foot Ulcer Prevention Diabetes Care

manufactured on the basis of both mea-sured barefoot plantar pressure andfoot shape prevent plantar ulceration

at MTHs in high-risk patients better thancurrent Medicare-approved orthosesData from barefoot plantar pressure

measurement should be used as de-scribed by Owings et al (17) in the designof orthoses for high-risk patients with di-abetes and neuropathy

Acknowledgments The contribution of Joseph LLoomis DIApedia LLC to this project overthe last 10 years is very much appreciated Thecontribution of all participants in the study isgratefully acknowledged and greatly appreci-ated The study would not have been possiblewithout the hard work of the site investigatorsand study coordinators which is also greatlyappreciated They were as follows Blair Med-ical Altoona PA Harold L Penny (PI) JuliaBenton (Research Manager) Heidi Sprouse (Re-search Coordinator) Carl T Hayden VA MedicalResearch Foundation Phoenix AZ Robert GFrykberg (PI) Shannon Fears (Research Co-ordinator) Center For Clinical Research SanFrancisco CA Alexander M Reyzelman (PI)Gayana Sarkisova (Research Coordinator)Cleveland Clinic Foundation Cleveland OHGeorgeanne G Botek (PI) Tammy Owings (Re-search Coordinator) Complete Family FootCare McAllen TX Joseph M Caporusso (PI)Joseph F Bender Bryan J Prukop (Sub-I) TracyRodriguez Brenda Hernandez (Research Coor-dinators) Diabetic Foot and Wound CenterDenver CO Eric D Jaakola (PI) Jeffrey L Jensen(PI) Brian Gillin (CPed) Patricia Nelson (Re-search Coordinator) Edward Hines Jr VA Hos-pital Hines IL Rodney M Stuck (PI) ColeenNapolitano Nicholas Vogelsang (Sub-I) AnneGarabedian Ana Zuluaga (Research Coordina-tors) Innovative Medical Technologies Inc LosAngeles CA Gabriel J Halperin (PI) Jack Morgan(Sub-I) Francis Morfin (Research Coordinator)Southern Arizona Limb Salvage Alliance TucsonAZ David G Armstrong (PI) Maricela CervantezMarcy Watchman (Research Coordinators)Temple University School of Podiatric MedicinePhiladelphia PA James B McGuire (PI) JinsupSong (Sub-I) Dana Tango (Research Coordinator)Weil Foot and Ankle Institute DesPlaines ILLowell S Weil Sr (PI) Jeffrey Baker GeorgeEnriquez Erin Klein (Sub-I) Robert DeLeon JessicaKnight Usman Akram (Research Assistants)Iwona Putowska Francesca Rivera (ResearchCoordinators)

A critical contribution to this project was madeby the blinded photograph adjudicatorsMichael J Mueller (Washington UniversitySchool of Medicine St Louis MO) NeilM Scheffler (Baltimore Podiatry Group BaltimoreMD) Stephanie CS Wu (Rosalind Franklin Univer-sity Chicago IL) The authors thank JamesWrobelDPM MS (University of Michigan Ann Arbor MI)for providing data and safety oversight for theduration of the study and to members of the adhoc data and safety monitoring board assembledto review the interim data analysis BenjaminWilfondMD (Professor Department of PediatricsUniversity of Washington [Chair]) Ann MelvinMD MPH (Associate Professor of PediatricsDivision of Infectious Disease University ofWashington) Patrick Heagerty PhD (ProfessorBiostatistics University of Washington) andSusan Ellenberg PhD (Professor Biostatistics Uni-versity of Pennsylvania) The patient education

Figure 2mdashA Combined end point Kaplan-Meier curve B Ulcer end point Kaplan-Meier curveC Nonulcerative lesion end point Kaplan-Meier curve (A high-quality color representation ofthis figure is available in the online issue)

carediabetesjournalsorg Ulbrecht and Associates 7

manufactured on the basis of both mea-sured barefoot plantar pressure andfoot shape prevent plantar ulceration

at MTHs in high-risk patients better thancurrent Medicare-approved orthosesData from barefoot plantar pressure

measurement should be used as de-scribed by Owings et al (17) in the designof orthoses for high-risk patients with di-abetes and neuropathy

Acknowledgments The contribution of Joseph LLoomis DIApedia LLC to this project overthe last 10 years is very much appreciated Thecontribution of all participants in the study isgratefully acknowledged and greatly appreci-ated The study would not have been possiblewithout the hard work of the site investigatorsand study coordinators which is also greatlyappreciated They were as follows Blair Med-ical Altoona PA Harold L Penny (PI) JuliaBenton (Research Manager) Heidi Sprouse (Re-search Coordinator) Carl T Hayden VA MedicalResearch Foundation Phoenix AZ Robert GFrykberg (PI) Shannon Fears (Research Co-ordinator) Center For Clinical Research SanFrancisco CA Alexander M Reyzelman (PI)Gayana Sarkisova (Research Coordinator)Cleveland Clinic Foundation Cleveland OHGeorgeanne G Botek (PI) Tammy Owings (Re-search Coordinator) Complete Family FootCare McAllen TX Joseph M Caporusso (PI)Joseph F Bender Bryan J Prukop (Sub-I) TracyRodriguez Brenda Hernandez (Research Coor-dinators) Diabetic Foot and Wound CenterDenver CO Eric D Jaakola (PI) Jeffrey L Jensen(PI) Brian Gillin (CPed) Patricia Nelson (Re-search Coordinator) Edward Hines Jr VA Hos-pital Hines IL Rodney M Stuck (PI) ColeenNapolitano Nicholas Vogelsang (Sub-I) AnneGarabedian Ana Zuluaga (Research Coordina-tors) Innovative Medical Technologies Inc LosAngeles CA Gabriel J Halperin (PI) Jack Morgan(Sub-I) Francis Morfin (Research Coordinator)Southern Arizona Limb Salvage Alliance TucsonAZ David G Armstrong (PI) Maricela CervantezMarcy Watchman (Research Coordinators)Temple University School of Podiatric MedicinePhiladelphia PA James B McGuire (PI) JinsupSong (Sub-I) Dana Tango (Research Coordinator)Weil Foot and Ankle Institute DesPlaines ILLowell S Weil Sr (PI) Jeffrey Baker GeorgeEnriquez Erin Klein (Sub-I) Robert DeLeon JessicaKnight Usman Akram (Research Assistants)Iwona Putowska Francesca Rivera (ResearchCoordinators)

A critical contribution to this project was madeby the blinded photograph adjudicatorsMichael J Mueller (Washington UniversitySchool of Medicine St Louis MO) NeilM Scheffler (Baltimore Podiatry Group BaltimoreMD) Stephanie CS Wu (Rosalind Franklin Univer-sity Chicago IL) The authors thank JamesWrobelDPM MS (University of Michigan Ann Arbor MI)for providing data and safety oversight for theduration of the study and to members of the adhoc data and safety monitoring board assembledto review the interim data analysis BenjaminWilfondMD (Professor Department of PediatricsUniversity of Washington [Chair]) Ann MelvinMD MPH (Associate Professor of PediatricsDivision of Infectious Disease University ofWashington) Patrick Heagerty PhD (ProfessorBiostatistics University of Washington) andSusan Ellenberg PhD (Professor Biostatistics Uni-versity of Pennsylvania) The patient education

Figure 2mdashA Combined end point Kaplan-Meier curve B Ulcer end point Kaplan-Meier curveC Nonulcerative lesion end point Kaplan-Meier curve (A high-quality color representation ofthis figure is available in the online issue)

carediabetesjournalsorg Ulbrecht and Associates 7

materials were developed with the help of thelate Richard Rubin PhD (The Johnrsquos Hopkins Uni-versity School of Medicine Baltimore MD)whose input is hereby acknowledged withgratitude Last the authors thank the staff atDIApedia LLC Alesia Dumas Heidi McClellandAngie Morrison and Linda Zedalis who wereresponsible for overall trial coordinationFunding This study was supported by Grant2R44-DK-059074 from the National Institutes ofHealth (NIDDK) to DIApedia LLCDuality of Interest JSU TH and PRC allhave equity in DIApedia LLC which designedand manufactured the experimental orthosesNo other potential conflicts of interest relevantto this article were reportedAuthor Contributions All authors partici-pated in the design of the trial JSU servedas the PI for the trial overall and wrote themanuscript TH managed clinical site interac-tions and edited the manuscript DTM con-ducted the statistical analysis and edited themanuscript PRC wrote the manuscript JSUis the guarantor of this work and as such hadfull access to all the data in the study and takesresponsibility for the integrity of the data andthe accuracy of the data analysis

References1 Pecoraro RE Reiber GE Burgess EM Path-ways to diabetic limb amputation Basis for pre-vention Diabetes Care 199013513ndash5212 Driver VR Yao M Discussion The economicsof limb salvage in diabetes Plast Reconstr Surg2011127(Suppl 1)296Sndash297S3 Driver VR Fabbi M Lavery LA Gibbons GThe costs of diabetic foot the economic casefor the limb salvage team J Vasc Surg 201052(Suppl)17Sndash22S4 Gordois A Scuffham P Shearer A Oglesby ATobian JA The health care costs of diabetic pe-ripheral neuropathy in the US Diabetes Care2003261790ndash17955 Dubsky M Jirkovska A Bem R et al Riskfactors for recurrence of diabetic foot ulcersprospective follow-up analysis in the Eurodialesubgroup Int Wound J 201310555ndash5616 Kloos C Hagen F Lindloh C et al Cognitivefunction is not associated with recurrent foot

ulcers in patients with diabetes and neuropa-thy Diabetes Care 200932894ndash8967 Maciejewski ML Reiber GE Smith DGWallace C Hayes S Boyko EJ Effectiveness ofdiabetic therapeutic footwear in preventingreulceration Diabetes Care 2004271774ndash17828 Edmonds ME Blundell MP Morris METhomas EM Cotton LT Watkins PJ Improvedsurvival of the diabetic foot the role of a spe-cialized foot clinic Q J Med 198660763ndash7719 Cowley MS Boyko EJ Shofer JB Ahroni JHLedoux WR Foot ulcer risk and location in re-lation to prospective clinical assessment of footshape and mobility among persons with diabe-tes Diabetes Res Clin Pract 200882226ndash23210 Arts ML Waaijman R de Haart MKeukenkamp R Nollet F Bus SA Offloading effectof therapeutic footwear in patients with diabeticneuropathy at high risk for plantar foot ulcera-tion Diabet Med 2012291534ndash154111 Altindas M Kilic A Cinar C Bingol UAOzturk G The epidemiology of foot wounds inpatients with diabetes a description of 600 con-secutive patients in Turkey J Foot Ankle Surg201150146ndash15212 Strbova L Krahulec BWaczulıkova I Gaspar LAmbrozy E [Characteristics of foot ulcers in dia-betic patients] Vnitr Lek 200955918ndash924 [inSlovak]13 Prompers L Huijberts M Apelqvist J et alHigh prevalence of ischaemia infection and se-rious comorbidity in patients with diabetic footdisease in Europe Baseline results from theEurodiale study Diabetologia 20075018ndash2514 Pham H Armstrong DG Harvey C HarklessLB Giurini JM Veves A Screening techniques toidentify people at high risk for diabetic foot ul-ceration a prospective multicenter trial Diabe-tes Care 200023606ndash61115 Veves A Murray HJ Young MJ Boulton AJThe risk of foot ulceration in diabetic patientswith high foot pressure a prospective studyDiabetologia 199235660ndash66316 Bus SA Valk GD van Deursen RW et al Theeffectiveness of footwear and offloading inter-ventions to prevent and heal foot ulcers andreduce plantar pressure in diabetes a system-atic review Diabetes Metab Res Rev 200824(Suppl 1)S162ndashS180

17 Owings TM Woerner JL Frampton JDCavanagh PR Botek G Custom therapeutic in-soles based on both foot shape and plantarpressure measurement provide enhanced pres-sure relief Diabetes Care 200831839ndash84418 Boulton AJ Armstrong DG Albert SF et alAmerican Diabetes Association American Asso-ciation of Clinical Endocrinologists Comprehen-sive foot examination and risk assessmenta report of the task force of the foot care in-terest group of the American Diabetes Associa-tion with endorsement by the AmericanAssociation of Clinical Endocrinologists Diabe-tes Care 2008311679ndash168519 Lavery LA Higgins KR Lanctot DR et al Pre-venting diabetic foot ulcer recurrence in high-risk patients use of temperature monitoringas a self-assessment tool Diabetes Care 20073014ndash2020 Bus SA Waaijman R Arts ML et al Effect ofcustom-made footwear on foot ulcer recur-rence in diabetes a multicenter randomizedcontrolled trial Diabetes Care 2013364109ndash411621 Cavanagh PR Derr JA Ulbrecht JS MaserRE Orchard TJ Problems with gait and posturein neuropathic patients with insulin-dependentdiabetes mellitus Diabet Med 19929469ndash47422 Vileikyte L Peyrot M Bundy C et al Thedevelopment and validation of a neuropathy-and foot ulcer-specific quality of life instrumentDiabetes Care 2003262549ndash255523 Vileikyte L Gonzalez JS Leventhal H et alPatient interpretation of neuropathy (PIN)questionnaire an instrument for assessmentof cognitive and emotional factors associatedwith foot self-care Diabetes Care 2006292617ndash262424 Moher D Hopewell S Schulz KF et alCONSORT CONSORT 2010 explanation andelaboration updated guidelines for reportingparallel group randomised trials Int J Surg20121028ndash5525 Waaijman R Keukenkamp R de Haart MPolomski WP Nollet F Bus SA Adherence towearing prescription custom-made footwearin patients with diabetes at high risk for plantarfoot ulceration Diabetes Care 2013361613ndash1618

8 Footwear for Diabetic Foot Ulcer Prevention Diabetes Care