Prevention of Recurrent FootUlcers With Plantar Pressure–Based In-Shoe Orthoses: TheCareFUL Prevention MulticenterRandomized Controlled TrialDiabetes Care 2014;37:1982–1989 | DOI: 10.2337/dc13-2956

OBJECTIVE

To assess the efficacy of in-shoe orthoses that were designed based on shape andbarefoot plantar pressure in reducing the incidence of submetatarsal head plantarulcers in people with diabetes, peripheral neuropathy, and a history of similarprior ulceration.

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 months,until 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 = 0.13) in favor of the experimen-tal orthoses. This trend was due to a marked difference in ulcer occurrence (P =0.007) but no difference in the rate of nonulcerative lesions (P = 0.76). At 180 days,the ulcer prevention effect of the experimental orthoses was already significant(P = 0.003) when compared with control, and the benefit of the experimentalorthoses with respect to the composite end point was also significant (P =0.042). The hazard ratio was 3.4 (95% CI 1.3–8.7) 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 pressure–based 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 SportsMedicine,University of Washington, Seattle, WA

Corresponding author: Peter R. Cavanagh,cavanagh@u.washington.edu.

Received 17 December 2013 and accepted 14March 2014.

Clinical trial reg. no.NCT00803608, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc13-2956/-/DC1.

© 2014 by the American Diabetes Association.See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

Jan S. Ulbrecht,1,2,3,4 Timothy Hurley,4

David T. Mauger,5 and

Peter R. Cavanagh4,6

1982 Diabetes Care Volume 37, July 2014

PATH

OPHYSIOLO

GY/COMPLICATIONS

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 (2–4). Afteran initial foot ulcer, the risk of reulcera-tion is extraordinarily high (5–7), insome studies .80% after 3 years (8).Approximately 40% (14–78%) of diabeticfoot ulcers are located on the plan-tar surface related to metatarsal heads(MTHs) (9–13), 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 U.S. 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 patient’s 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 outpa-tient clinic sites specializing in diabeticfoot care across the U.S. (two each inPennsylvania, Illinois, California, and

Arizona and one each in Ohio, Texas,and Colorado) and included academicmedical centers, Veterans Affairs clinics,and private practice podiatry clinics(Supplementary Appendix 1). All siteprincipal investigators (PIs) were clini-cians with significant experience manag-ing diabetes-related foot problems andhad prior experience conducting clinicaltrials.

Study ParticipantsMost subjects were patients at the coop-erating clinics and were recruited underinstitutional review board (IRB) approval.Local 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 ulcer;peak barefoot plantar pressure in thearea of this previous ulcer (the “index ul-cer”) .450 kPa; community ambulator;no 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 orthosis;no existing footwear intervention morecomplex than would be available throughthe study footwear and orthotic options(e.g., 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 emed D 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 a3:1:1:1 ratio (experimental orthosis:control orthosis 1:control orthosis 2:control orthosis 3; see below). Random-ization was stratified by site and sex.Blocked randomization (block size 6)was used within strata. The randomiza-tion tables were developed by one ofthe investigators (D.T.M.) who was not

directly involved in managing the trial.Randomization assignment was givenby the coordinating center to eachsite for each subject after eligibilitywas confirmed. The study PI (J.S.U.),study statistician (D.T.M.), patients,and adjudicators were blinded as tothe assignment of patients to treat-ment groups.

After randomization, visit two for dis-pensing of footwear occurred at 7.9 and7.8 weeks in the experimental and con-trol arms, respectively. During this time,the 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 education,particularly during the break-in period.The break-in process was formalized.Starting 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 16.5 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 http://www.clinicaltrials.gov (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 “shape only” 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

care.diabetesjournals.org Ulbrecht and Associates 1983

durometer) using a computer-aidedmanufacturing process. A laminatedfabric-PPT (polyurethane foam) top coveris added, and the orthoses are hand-finished and shipped back to the clini-cal site for dispensing. For this study,the design algorithm focused on off-loading the submetatarsal head region.We chose to include standard ortho-

ses from three different manufacturersin the control arm of the study in orderto make the results more generalizable.However, 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, bars,reliefs, etc., as they would do in theirclinical practice.In all cases, subjects received three

pairs of identical orthoses to be rotatedwhile using the primary study footwearaccording to a written rotation protocol,changing the numbered orthoses in aset rotation every month. Subjectswere offered one of two footwear mod-els manufactured by p.w. Minor (Bata-via, NY) regardless of study groupassignment (Performance Walker andLeisure Time). The experimental insolesrequired 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 Pedors Classic (Marietta,GA) shoes with 9.5-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 (e.g., Neos Over-shoe) in inclement weather conditions.The 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 permit anintent-to-treat analysis. Shoes and/ororthoses could be replaced using priordata stored by the manufacturers if ei-ther were showing excessive wear in theopinion 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 problems.Study coordinators used worksheets toencourage adherence and also usednonthreatening open-ended questionsin their conversationswith study subjects.An 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 assignment,and 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 absent/nonulcerative lesion/ulcer; involving/not involving the plan-tar surface (defined as involving theweight-bearing surface of the foot);and related to MTH/not 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 “allowed”such 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 details,information needed for inclusion/exclu-sion and for prescription of orthoses andfootwear, as well as ankle–brachial in-dex (ABI) (values absent due to noncom-pressible vessels were treated asmissing data), standardized foot examfor deformity (in the analyses, the de-formity index used was for the footwith the primary end point, or rightfoot when no end point occurred) (Sup-plementary 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,

1984 Footwear for Diabetic Foot Ulcer Prevention Diabetes Care Volume 37, July 2014

Pennsylvania State University. Data werevalidated by the coordinating centeragainst the primary source documents.For 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 lesion.Secondary 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 9.2 (SAS Inc.,Cary, NC).The target sample size was 286 ran-

domized patients, calculated to provide80% statistical power for a two-sided,0.05 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 anticipated,our 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 times.Such was the case in the current study.During 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 (Table 1) be-tween randomized subjects receivingfootwear and not receiving footwear,except that those not receiving foot-wear reported higher scores for avoid-ing foot-damaging behaviors (0.96 vs.0.90; P = 0.03).

At baseline, the mean ABI was higherin the control group (P = 0.02), andsubjects entering the control groupshowed a trend toward higher scoreson avoiding foot-damaging behaviors(P = 0.07); both these biases would favorbetter outcomes in the control group.The 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-ion/wishes of the prescribing clinician. Bydesign, all experimental orthoses hadpatient-specificmetatarsal bars and reliefs(17). Nine experimental and five controlsubjects received replacement/supple-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 = 0.13). This trend is due to amarked difference in ulcer occurrence(P = 0.007, greater in control) (Fig. 2B),whereas there is no difference in therate of nonulcerative lesions (P = 0.76)(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 = 0.003) 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 = 0.042).

The P values at 1 year, the point atwhich footwear is usually replaced,were P = 0.073 and P = 0.0041 for thecomposite and ulcer end points, respec-tively. Across the full study, a primaryend point occurred in 37.9% (25 of 66)of subjects in the experimental arm (ul-cers in 9.1%; 6 of 66) and in 45.3% (29 of64) of subjects in the control group (ul-cers in 25.0%; 16 of 64). The hazard ratiowas 3.4 (95% CI 1.3–8.7) 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 1,131,1,042, and 984 kPa in feet that devel-oped ulcers, nonulcerative lesions, andno end point, respectively (P = 0.04). Ineach case, the barefoot plantar pres-sures trended higher in the experimen-tal compared with control groups (1,170vs. 1,116 kPa for ulcers and 1,071 vs.999 kPa for nonulcerative lesions; P =0.3).

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

care.diabetesjournals.org Ulbrecht and Associates 1985

the duration of the study. All subjectsreported better average foot self-carehabits after being instructed (P , 0.01baseline 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 (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 3.4(95% CI 1.3–8.7) 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 = 0.04, P =0.07, and P = 0.13 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 footwear.Furthermore, 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 1—CONSORT diagram.

1986 Footwear for Diabetic Foot Ulcer Prevention Diabetes Care Volume 37, July 2014

more consistently comply with footwearuse, use of a pedometer to manageactivity, etc.The 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 (19,20).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 after;6months of wear.After 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 footwear,etc. 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 ortho-tist or pedorthist. Examination of theefficacy of remotely produced pressure-based orthoses in comparison with suchhandcrafted orthoses would be of inter-est, since the manufacturing cost of thelatter is much higher.

Taken together with the recent stud-ies from the Netherlands (20,25), ourdata offer some clarification of the pre-viously uncertain (16,25) foundation forthe effectiveness of diabetic footwear.To 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 sample.Future studies should examine other re-gions of the foot where similar relation-ships between plantar pressure reductionand risk reduction may be expected(16,20). In addition, a future study quan-titatively examining the degradation inpressure relief of various orthosesas a function of time would inform guide-lines for replacement/reimbursement.Although a definitive statement willrequire a formal cost-benefit analysis,the huge costs associatedwith foot ulcersand subsequent amputation in diabeticpatients (2–4) (estimated to be $10.7billion in 2001) (4) suggest that clinicaluse of the orthoses tested in this studywould result in significant cost savings tothe health care system.

In summary, this study demonstratesthat orthoses individually designed and

Table 1—Baseline demographic and other characteristics of subjects whoreceived footwear

Characteristic Experimental group Control group

Number of subjects 66 64

Number of male subjects 50 (75.8%) 52 (81.3%)

Age in years* (range) 60.5 6 10.1 (33–83) 58.5 6 10.7 (35–88)

BMI (kg/m2)* 32.3 6 7.1 31.4 6 5.5

Smoking 6 (9.1%) 12 (18.8%)

EthnicityHispanic or Latino 21 (31.8%) 20 (30.2%)

RaceWhite† 55 (83.3%) 51 (79.7%)African American† 10 (15.2%) 11 (17.2%)Other† 1 (1.5%) 2 (3.1%)

SocioeconomicAt least high school graduate 49 (74.2%) 52 (82.3%)Graduated college 12 (18.2%) 18 (28.1%)Not living alone 50 (75.8%) 47 (73.4%)

ABI*‡ 1.05 6 0.16 1.13 6 0.18

Index ulcer location§MTH 1 36 (54.5%) 29 (45.3%)MTH 2 13 (19.7%) 10 (15.6%)MTH 3 2 (3.0%) 11 (17.2%)MTH 4 5 (7.6%) 8 (12.5%)MTH 5 13 (19.7%) 11 (17.2%)

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)* 1,109 6 173 1,085 6 191

Prior minor amputation|| 21 (31.8%) 24 (37.5%)

Foot deformity index*¶ 28.4 6 14.6 28.9 6 17.3

NeuroQOL*#Physical symptoms 1.56 6 0.85 1.38 6 0.87Psychological symptoms 1.57 6 1.13 1.64 6 1.16

Foot self-care*,**Preventive 0.66 6 0.21 0.68 6 0.20Avoid damaging behaviors 0.88 6 0.14 0.92 6 0.12

FallsNumber recalling a fall last year 28 (42.4%) 34 (53.1%)Number who worry about falling (%)* 47.1 6 31.2 45.8 6 33.9

NeuroQOL, neuropathy-specific quality of life. *Mean 6 SD. †Some selected more than onerace. ‡Average of all legs. §Some had more than one index ulcer. ||See exclusion criteria. ¶Scale0–100. #Scale 0–4, 0 = no symptoms. **Scale 0–1, 1 = best behavior.

care.diabetesjournals.org Ulbrecht and Associates 1987

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 orthoses.Data 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 L.Loomis, DIApedia LLC, to this project overthe past 10 years is very much appreciated.The contribution 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 G.Frykberg (PI), Shannon Fears (Research Co-ordinator); Center For Clinical Research, SanFrancisco, CA: Alexander M. Reyzelman (PI),Gayana Sarkisova (Research Coordinator);Cleveland Clinic Foundation, Cleveland, OH:Georgeanne 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 Center,Denver, 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), JackMorgan(Sub-I), Francis Morfin (Research Coordinator);Southern Arizona Limb Salvage Alliance, Tucson,AZ: David G. Armstrong (PI), Maricela Cervantez,Marcy Watchman (Research Coordinators);Temple University School of Podiatric Medicine,Philadelphia, PA: James B. McGuire (PI), JinsupSong (Sub-I), Dana Tango (Research Coordinator);Weil Foot and Ankle Institute, Des Plaines, IL:Lowell 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 adjudicators:Michael J. Mueller (Washington UniversitySchool of Medicine, St. Louis, MO), NeilM. Scheffler (Baltimore Podiatry Group, Baltimore,MD), Stephanie C.S. Wu (Rosalind Franklin Univer-sity, Chicago, IL). The authors thank JamesWrobel,DPM, 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: BenjaminWilfond,MD (Professor, Department of Pediatrics,University of Washington [Chair]), Ann Melvin,MD, MPH (Associate Professor of Pediatrics,Division of Infectious Disease, University ofWashington), Patrick Heagerty, PhD (Professor,Biostatistics, University of Washington), andSusan Ellenberg, PhD (Professor, Biostatistics, Uni-versity of Pennsylvania). The patient education

Figure 2—A: Combined end point Kaplan-Meier curve. B: Ulcer end point Kaplan-Meier curve.C: Nonulcerative lesion end point Kaplan-Meier curve.

1988 Footwear for Diabetic Foot Ulcer Prevention Diabetes Care Volume 37, July 2014

materials were developed with the help of thelate Richard Rubin, PhD (The Johns HopkinsUniversity School of Medicine, Baltimore, MD),whose input is hereby acknowledged withgratitude. Last, the authors thank the staff atDIApedia LLC, Alesia Dumas, Heidi McClelland,Angie Morrison, and Linda Zedalis, who wereresponsible for overall trial coordination.Funding. This study was supported by Grant2R44-DK-059074 from the National Institutes ofHealth (NIDDK) to DIApedia LLC.Duality of Interest. J.S.U., T.H., and P.R.C. allhave equity in DIApedia LLC, which designedand manufactured the experimental orthoses.No other potential conflicts of interest relevantto this article were reported.Author Contributions. All authors partici-pated in the design of the trial. J.S.U. servedas the PI for the trial overall and wrote themanuscript. T.H. managed clinical site interac-tions and edited the manuscript. D.T.M. con-ducted the statistical analysis and edited themanuscript. P.R.C. wrote the manuscript. J.S.U.is 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.

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care.diabetesjournals.org Ulbrecht and Associates 1989