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Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program APPENDIX D. EVIDENCE TABLES Table 1. Study Characteristics Table

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Type Funding Source Length of Follow-up Abidia 200349 Inclusion: diabetes; ischemic lower extremity N=16 (of 18 randomized) Intervention (n=9): HBOT; 2.4 ATA Allocation concealment: ulcers (>1 cm and <10 cm in maximum Age (years): 71 for 90 minutes on 30 occasions Adequate United Kingdom diameter); no signs of healing for >6 weeks Gender (% male): 50 over 6 weeks; multi-place chamber despite optimum medical management; Race/ethnicity: NR Blinding: Patients, Funding Source: NR occlusive arterial disease confirmed by ankle- BMI: NR Control (n=9): sham (hyperbaric investigators, outcome brachial pressure index <0.8 (or great toe <0.7 if Pre-albumin: NR air) assessors Therapy Type: calf vessels incompressible) HbA1c (%): NR ALL: specialized multidisciplinary Intention to treat analysis Hyperbaric oxygen Smoking: 19% wound management program (ITT): No, two withdrawals (HBOT) Exclusion: planned , # Work days missed: NR (off-loading, debridement, moist not included in analysis , or thrombolysis ABI: <0.8 for inclusion dressing) Wound location: foot Withdrawals/dropouts Wound type: ischemic diabetic Antibiotic Use: As needed adequately described: Yes Wound size, mm2 (median): HBOT 106; Treatment Duration: 6 weeks control 78 Follow-up Duration: 1 year Wound grade (Wagner*, %): Grade I 6; Study Withdrawal (%): 20 (n=2) II 94 Treatment Compliance: “The Wound duration, months: HBOT 6; protocol was strictly followed control 9 throughout the study” Comorbid conditions (%): History of CAD/CVD: (previous bypass 31, angioplasty 6) History of DM: 100 History of : minor 19

112 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Agrawal 200928 Inclusion: ≥30 years of age; Wagner stage I, II, N=28 Intervention (n=14): rhPDGF 0.01% Allocation concealment: III, or IV ulcers; foot ulcer duration >3 months; Age (years): 55 gel at 2.2ug/cm2/day Unclear India free of ; adequate lower-limb blood Gender (% male): 68 supply (transcutaneous oxygen tension ≥30 Race/ethnicity: NR Comparator (n=14): placebo gel at Blinding: Unclear Funding Source: NR 2.2ug/cm2/day mmHg), no or moderate peripheral vascular BMI: 25.7 Intention to treat analysis Therapy Type: disease Pre-albumin: NR ALL: standard regimen of high- (ITT): No Platelet-derived HbA1c (%): 8.8 quality care (included glycemic Growth Factor Exclusion: active neoplastic disease; diagnosis Smoking: NR Withdrawals/dropouts of active infection characterized by warmth, control, debridement, dressings, # Work days missed: NR pressure relief) adequately described: , lymphangitis, lymphadenopathy, ABI: NR Partial – 5 withdrawals oedema, or pain; received immunosuppressive Wound location: foot Antibiotic Use: as needed from the control group therapy during the preceding three months; Wound type: diabetic Treatment Duration: 12 weeks with no reason for liver disease, pulmonary tuberculosis, Wound size: 41.5 cm2 (ulcer size Follow-up Duration: NR withdrawal thyroid disorder uremia, alcoholism or significantly larger in study group Study Withdrawal (%): 18 (all from renal insufficiency; undergoing vascular p=0.003) control group at week 12) reconstruction or receiving steroid or Wound grade: NR Treatment Compliance: NR anticoagulant therapy Wound duration: NR Infection: excluded Comorbid conditions (%): Diabetes: 100 Aminian 200027 Inclusion: chronic non-healing diabetic ulcers N=12 ulcers (7 patients) of 14 ulcers (9 Intervention (n=7 ulcers): Allocation concealment: of at least eight weeks duration; controlled patients) randomized autologous platelet extract (APE) Inadequate Iran blood sugar; normal peripheral blood platelet Age (years): 60 + silver sulfadiazine dressing 12 Blinding: Unclear Funding Source: count (>150,000/cu mm); negative history of Gender (% male): 100 hours on and 12 hours off malignancy Race/ethnicity: NR Government Comparator (n=5 ulcers): saline Intention to treat analysis BMI: NR (ITT): No Therapy Type: Exclusion: determined to have non-diabetic Pre-albumin: NR solution and silver sulfadiazine 12 Platelet-Derived ulcers hours on and 12 hours off Withdrawals/dropouts HbA1c (%): NR Growth Factor Smoking: NR ALL: supportive, conventional care adequately described: Yes # Work days missed: NR (debridement, blood sugar checked – 2 patients with 2 ulcers ABI: NR weekly, off-loading) excluded after entering Wound location: foot study (non-compliance, Wound type: diabetic ulcer Antibiotic Use: oral, if needed non-diabetic ulcer) Wound size: 5.9 cm2 Treatment Duration: 8 weeks Wound grade: NR Follow-up Duration: NR Wound duration: 12.9 wks Study Withdrawal (%): 22% Infection: NR Treatment Compliance: 1/9 pts Comorbid conditions (%): withdrawn for non-compliance Diabetes: 100

113 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Armstrong 200581 Inclusion: age ≥18; wound from diabetic foot N=162 Intervention (n=77): VAC system; Allocation concealment: Apelqvist 200882 amputation to transmetatarsal level of foot; Age (years): 59 dressing changes every 48 hrs Adequate evidence of adequate perfusion (transcutaneous Gender (% male): 81 United States (18 Comparator (n=85): standard Blinding: Partial O2 on dorsum of foot ≥30 mmHg or ABI ≥0.7 Race/ethnicity (%): Non-Hispanic white: sites) care (moist wound therapy with (independently assessed and ≤1.2, and toe pressure ≥30 mmHg); 48; African-American: 17; Mexican- alginates, hydrocolloids, foams, or and confirmed closure Funding Source: University of Texas grade 2 or 3 in depth American: 32; Native American: 3 hydrogels; dressing changes every with digital planimetry) Industry (not involved BMI: 31 Exclusion: active Charcot arthropathy of day unless otherwise advised in analysis or write-up Pre-albumin (g/L): 0.19 Intention to treat foot; wound from , venous insufficiency, of manuscript; did not HbA c (%): 8.2 ALL: off-loading therapy as analysis (ITT): Yes – no untreated cellulitis or osteomyelitis, collagen 1 maintain veto power Smoking: 9% indicated; sharp debridement at withdrawals vascular disease, malignant disease, or over final article) # Work days missed: NR randomization and as needed uncontrolled hyperglycemia (HbA c >12%); 1 ABI: 1.1 Withdrawals/dropouts treated with corticosteroids, immunosuppressive Therapy Type: Wound location: foot Antibiotic Use: NR adequately described: Yes drugs, or chemotherapy; VAC therapy in past Negative Pressure Wound type: amputation Treatment Duration: wound closure – no withdrawals 30 days, present or previous (past 30 days) Wound Therapy Wound size: 20.7 cm2 or 112 days treatment with growth factors; normothermic Wound grade: U of Texas 2/3 Wound Follow-up Duration: none therapy, hyperbaric medicine, or bioengineered duration: 1.5 months Study Withdrawal (%): 0 tissue Comorbid conditions (%): Treatment Compliance: NR History of DM: 100 (90% T2) Belcaro 201038 Inclusion: Venous Ulcer Patients: N=82 Intervention (n=44 VU, n=34 Allocation concealment: Venous Ulcer (VU) Patients: chronic venous Age (years): 47 DU): silver ointment around and Unclear Italy ulcers, venous microangiopathy, and peri- Gender (% male): 46 at edges of ulcerated area twice Blinding: Unclear Funding Source: NR malleaolar ulcerations Diabetic Ulcer Patients: N=66 daily after noninvasive washing; Diabetic Ulcer (DU) Patients: diabetic Age (years): 55.9 bandage and elastic stocking Intention to treat Therapy Type: Silver microangiopathy and plantar ulcers due Gender (% male): 44 analysis (ITT): Yes (no Oxide Ointment Comparator (n=38 VU, n=32 to reduced arterial pressure, diabetic Both Groups: withdrawals) DU): cleansing & wound care; microangiopahty and neuropathy, and localized Race/ethnicity: NR compression (mild for DU) infection BMI: NR Withdrawals/dropouts adequately described: Yes Pre-albumin: NR Antibiotic Use: NR Exclusion: (none) HbA c (%): NR Treatment Duration: 4 weeks Venous Ulcer Patients: venous thrombosis or 1 Smoking: NR Follow-up Duration: No follow-up arterial problems in past year; severe ischemia # Work days missed: NR post tx and (based on Doppler detected tibial ABI: NR Study Withdrawal (%): 0 pulse) Wound location: plantar (DU) Treatment Compliance: NR Diabetic Ulcer Patients: none reported Wound type: venous, diabetic Wound size: VU 3.2 cm2, DU 2.2 cm2 Wound grade: NR Wound duration: NR Comorbid conditions (%): NR

114 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Bhansali 200930 Inclusion: >20 years old with type 1 or 2 N=20 (24 ulcers) Intervention (n=13): 0.01% rh- Allocation concealment: diabetes; at least one neuropathic plantar ulcer Age (years): 51 PDGF-BB gel Unclear India of Wagner grade ≥ 2 without X-ray evidence of Gender (% male): 60 Comparator (n=11): standard Blinding: No (open label) Funding Source: osteomyelitis; ABI>0.9; controlled infection after Race/ethnicity: NR wound care (saline soaked Industry (provided run-in BMI: 24 Intention to treat analysis dressing) gel) Pre-albumin: NR (ITT): Yes Exclusion: none reported HbA c (%): 8.1 ALL: daily dressing changes; off- Therapy Type: 1 Withdrawals/dropouts Smoking: NR loading (85% total contact cast, Platelet-derived adequately described: Yes # Work days missed: NR 10% bedridden, 5% special shoe) Growth Factor ABI: 1.05 (none) Wound location: forefoot: 75%; mid: Antibiotic Use: As needed 20%; hind: 5% Treatment Duration: 20 weeks Wound type: diabetic Follow-up Duration: NR Wound size: 14.6 cm2 Study Withdrawal (%): 0 Wound grade: Wagner ≥ 2 Treatment Compliance: NR Wound duration: <4 weeks=20%; >4 weeks=80% Infection: 45% Comorbid conditions (%): History of DM: 100% History of amputation: 35% Bishop 199263 Inclusion: age 21 to 90 years; venous stasis N=86 (of 93 randomized) Intervention (n=29): 0.4% tripeptide Allocation concealment: ulcers of at least 3 months duration; surface Age (years): 56 copper complex cream Unclear United States (2 area 3 cm2 to 50 cm2; negative pregnancy test Gender (% male): 50 sites) Comparator (n=28): 1% silver Blinding: Yes (evaluator) and using adequate contraceptive (women of Race/ethnicity: white: 62; black: 33; sulphadiazine cream Funding Source: childbearing age) other: 6 Intention to treat analysis Industry BMI: NR Placebo (n=29): tripeptide vehicle (ITT): No Exclusion: to any components Pre-albumin: NR of test medication; >105 bacteria/gram Therapy Type: Silver HbA c (%): NR ALL: applied daily following saline Withdrawals/dropouts of tissue in the ulcer; systemic sepsis 1 Products Smoking: 33.7% currently rinse; non-adherent dressing and adequately described: or presence of bone infection; ABI<0.5; # Work days missed: NR elastic wrap; limb elevated when Partial (3 were immediate hypercupremia (Wilson’s disease); systemic ABI: NR sitting; no standing >2 hrs dropouts; 4 additional immunosuppressive or cytotoxic therapy; patients did not complete Wound location: “lower extremity” Antibiotic Use: NR insulin-dependent diabetes mellitus the trial; reasons not Wound type: venous stasis Treatment Duration: 4 weeks 2 provided) Wound size: 10.5 cm Follow-up Duration: 1 year Wound grade: NR Study Withdrawal (%): 7.5 Wound duration: 46.4 months Treatment Compliance: patient Comorbid conditions (%): diary and medication weighed at History of DM: 9% end of study; results NR

115 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Blair 198864 Inclusion: ulcers up to 10 cm2 N=60 Intervention (n=30): silver Allocation concealment: Age (years): 69 sulphadiazine dressing (Flamazine) Adequate United Kingdom Exclusion: ABI<0.8 Gender (% male): NR Comparator (n=30): non-adherent Blinding: Unclear Funding Source: NR Race/ethnicity: NR and non-occlusive dressing BMI: NR Intention to treat analysis Therapy Type: Silver Pre-albumin: NR ALL: out-patient treatment; (ITT): Yes Products HbA c (%): NR dressings changed weekly in 1 Withdrawals/dropouts Smoking: NR venous ulcer clinic; standard high adequately described: Yes # Work days missed: NR pressure graduated compression ABI: NR bandage over the dressing Wound location: NR Wound type: venous Antibiotic Use: NR Wound size: 3.4 cm2 Treatment Duration: 12 weeks Wound grade: NR Follow-up Duration: none Wound duration: 26.2 months since Study Withdrawal (%): 7% ulcer was last healed Treatment Compliance: NR Comorbid conditions (%): NR Blume 200842 Inclusion: diabetic adults (18+); stage 2 or 3 N=335 (of 341 randomized) Intervention (n=172): NPWT - Allocation concealment: (Wagner’s) calcaneal, dorsal, or plantar foot Age (years): 59 vacuum-assisted closure therapy; Adequate United States and ulcer; ≥2 cm2 after debridement; adequate Gender (% male): 78 dressing changes every 48-72 hrs Canada (29 sites) Blinding: Patients and blood circulation (dorsum transcutaneous O Race/ethnicity (%): African-American: 2 Comparator (n=169): advanced physicians not blinded; Funding Source: test ≥30 mmHg); ABI 0.7-1.2 with toe pressure 15; Caucasian: 58; Hispanic: 24; Native moist wound therapy (AMWT) unclear if outcome Industry ≥30 mmHg or triphasic or biphasic Doppler American: 2; other: 1 assessment was blinded waveforms at ankle BMI: NR Off-load: NPWT 97%; AMWT 98% Therapy Type: Pre-albumin: 20.5 Intention to treat analysis Negative Pressure Exclusion: active Charcot disease; electrical, Antibiotic Use: NR (28% treated for HbA c (%): 8.2 (ITT): Modified (received Wound Therapy chemical, or radiation ; collagen 1 infection before randomization) Smoking: 19% at least one post-baseline vascular disease; ulcer malignancy; untreated Treatment Duration: 112 days # Work days missed: NR treatment) osteomyelitis; cellulitis; uncontrolled ABI: 1.0 Follow-up Duration: 3 and 9 hyperglycemia; inadequate lower extremity Wound location: calcaneal, dorsal, or months after closure Withdrawals/dropouts perfusion; normothermic or hyperbaric plantar Study Withdrawal (%): NPWT: adequately described: Yes oxygen therapy; use of corticosteroids, Wound type: diabetic ulcer 32%; AMWT: 25% immunosupressants, or chemotherapy; growth Wound size: 12.3 cm2 Treatment Compliance: 6/169 factor products; or dermal substitutes within Wound grade: 2 or 3 (4%) in NPWT group were non- 30 days; enzymatic debridement; pregnant or Wound duration: 202 days compliant vs. 0% in AMWT group nursing Comorbid conditions (%): (not defined) History of DM: 100

116 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Blume 201115 Inclusion: type 1 or 2 diabetes; over age 18 yrs; N=52 Intervention (n=33): formulated Allocation concealment: Wagner Grade 1 cutaneous lower extremity Age (years): 56 collagen gel (FCG) (combined 1 Unclear United States (22 ulcer; 1.5-10.0 cm2; present ≥6 wks; peripheral Gender (% male): 77 dose and 2 dose groups) sites) Blinding: Investigators neuropathy; adequate blood flow (TcpO Race/ethnicity (%): white 64, black 12, (NOTE: included 2nd intervention 2 were blinded; other study Funding Source: >40mmHg or toe pressure ≥40mmHg) Hispanic 23, other 2 arm with non-FDA product) personnel were not Industry BMI: 34 Exclusion: HbA c >12%; ulcer on heel; cellulitis; Comparator (n=19): standard care 1 Pre-albumin: NR Intention to treat analysis Therapy Type: biopsy positive for beta hemolytic streptococci (debride, moist dressing) HbA c (%): 8.0 (ITT): Yes for safety Collagen or total bacterial load >1X106 CFU/g; decrease 1 Smoking: NR ALL: debridement; 2 wk standard analysis; per-protocol for in ulcer size >30% from screening to Tx day 1 # Work days missed: NR care run-in; off-loading shoe other outcomes ABI: NR Wound location: 89% plantar Antibiotic Use: NR Withdrawals/dropouts Wound type: diabetic Treatment Duration: 12 weeks adequately described: Yes Wound size: 2.9 cm2 Follow-up Duration: None (including 2 in FCG group Wound duration: 15.1 months Study Withdrawal (%): 6/5 (8/124) for non-compliance) Comorbid conditions (%): Treatment Compliance: see WD History of DM: 100 Brigido 200674 Inclusion: full thickness (Wagner grade II) N=28 Intervention (n=14): Graftjacket Allocation concealment: chronic wound ≥6 weeks without epidermal Age (years): 64 (single application); mineral oil Unclear United States coverage; non-infected; palpable/ audible pulse Gender (% male): NR soaked fluff compression dressing Blinding: No Funding Source: NR to the lower extremity Race/ethnicity: NR changed on days 5, 10, and 15 BMI: NR then weekly assessment Intention to treat analysis Therapy Type: Exclusion: none reported Pre-albumin: NR (ITT): Yes Comparator (n=14): Curasol Collagen HbA c (%): 8.0 1 wound gel; gauze dressing; weekly Smoking: NR Withdrawals/dropouts debridement # Work days missed: NR adequately described: Yes – all patients completed ABI: NR ALL: initial sharp debridement; off- study Wound location: leg/foot loading with walking boot Wound type: mixed Wound size: NR Antibiotic Use: NR Wound grade: Wagner grade II Treatment Duration: 16 weeks Wound duration: NR Follow-up Duration: None Infection: excluded if infected Study Withdrawal (%): 0 Comorbid conditions (%): NR Treatment Compliance: NR

117 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Chang 200073 Inclusion: non-healing foot ulcer or required N=31 Intervention (n=21): meshed Allocation concealment: partial open foot amputation; ABI <0.5 prior to Age (years): 70 (N=10) or unmeshed (N=11) tissue Unclear United States surgery; underwent bypass or Gender (% male): 77 graft (Apligraf); non-adherent Blinding: No Funding Source: NR angioplasty within 60 days of inclusion Race/ethnicity (%): NR dressing, Unna boot & ace wrap; BMI: NR followed every 5-7 days (or more) Intention to treat analysis Therapy Type: Exclusion: ABI <0.7 after revascularization st HbA c (%): NR for 1 month; Unna boot dressing (ITT): Unclear surgery; recent steroid use; chemotherapy; 1 Biological Skin Smoking: NR changes each visit until graft previous radiation; wound <2.0 cm2; infected Equivalent # Work days missed: NR maturation Withdrawals/dropouts wound, necrotic tissue, exposed bone, or ABI: NR (see inclusion criteria) adequately described: exposed tendons Comparator (n=10): moist saline Wound type: previously ischemic Unclear if any dropouts gauze sponges with dry cotton wounds s/p revascularization surgery gauze wrapping; changed 2x/day Wound size: 4.8 cm2 Wound duration: NR Antibiotic Use: NR Infection: excluded Treatment Duration: wound closure Comorbid conditions (%): or ≥ 6 months after randomization History of DM: 58% Follow-up Duration: same History of amputation: 45% History of Study Withdrawal (%): NR PVD: 100% Treatment Compliance: NR History of renal failure: 39% d’Hemecourt 199835 Inclusion: ≥19 years old; type 1 or 2 diabetes; at N=172 Intervention (n=30): becaplermin Allocation concealment: least one full thickness (Stage 3 or 4) diabetic Age (years): 58 gel 100ug/g and standard care Unclear United States (10 ulcer of >8 weeks duration; wound size 1.0-10.0 Gender (% male): 74 sites) Comparator A (n=70): sodium Blinding: Yes – patients, cm2; adequate arterial circulation Race/ethnicity (%): white: 85; black: 10; carboxymethylcellulose Gel evaluators Funding Source: other: 5 Exclusion: osteomyelitis affecting target ulcer (NaCMC) and standard care Industry BMI: NR Intention to treat analysis area; >3 chronic ulcers present at baseline; non- Pre-albumin: NR Comparator B (n=68): standard (ITT): Yes Therapy Type: diabetic wounds; cancer at time of enrollment; HbA c (%): NR care – sharp debridement, saline Platelet-derived use of concomitant medications (corticosteroids, 1 Withdrawals/dropouts Smoking: NR gauze dressing changes every 12 Growth Factors chemotherapy, immunosuppressive agents); adequately described: Yes # Work days missed: NR hours, off-loading pregnant or nursing ABI: NR Wound location: right leg: 3%; left leg: Antibiotic Use: systemic control of 4%; right foot: 47%; left foot: 47% infection if present Wound type: diabetic ulcer Treatment Duration: 20 weeks Wound size: 3.2 cm2 Follow-up Duration: NR Wound grade: 97% Stage III Study Withdrawal (%): 24 Wound duration: 42.3 weeks Treatment Compliance: NR Infection: NR Comorbid conditions (%): Diabetes: 100

118 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up DiDomenico 201126 Inclusion: type 1 or 2 diabetes; Wagner grade 1 N=28 patients (29 wounds) Intervention (n=17 wounds): Allocation concealment: or University of Texas 1a ulcer; wound duration Age (years): NR Apligraf; up to 5 applications Unclear United States >4 weeks; area 0.5-4 cm2; HbA c <12; ABI Gender (% male): NR 1 Comparator (n=12 wounds): Blinding: Unclear Funding Source: >0.75; palpable pulses on the study foot; able to Race/ethnicity: NR Theraskin; up to 5 applications Industry comply with off-loading BMI: NR Intention to treat analysis Pre-albumin: NR ALL: debridement, off-loading; (ITT): Unclear Therapy Type: Exclusion: infection or gangrenous tissue or HbA c (%): NR dressing changes every other day Biological Skin abscesses; exposed bone, tendon, or joint 1 Withdrawals/dropouts Smoking: NR or daily, as needed capsule; non-diabetic etiology; use of topical Equivalent # Work days missed: NR adequately described: Yes medications that may affect graft material; ABI: NR Antibiotic Use: NR such as hyperbaric oxygen; Wound location: NR Treatment Duration: 12 weeks wound depth <9 mm Wound type: diabetic ulcer Follow-up Duration: to 20 weeks Wound size: 1.9 cm2 Study Withdrawal (%): NR Wound grade: see inclusion Treatment Compliance: NR Wound duration: see inclusion Comorbid conditions (%): NR Dimakakos 200965 Inclusion: leg ulcer classified as exclusively N=42 Intervention (n=21): non-adhesive Allocation concealment: infected and venous in origin Age (years): 60 silver-releasing foam Unclear Greece Gender (% male): 38 Exclusion: pregnancy; psychiatric disorders; Comparator (n=21): non-adhesive Blinding: Unclear Funding Source: NR Race/ethnicity: NR diabetes; collagen disease; steroid use; history foam BMI: NR Intention to treat analysis Therapy Type: Silver of ; ABPI<1 Pre-albumin: NR ALL: cleansing with sterile water (ITT): No withdrawals/ Dressing HbA1c (%): NR and 10% povidone iodine solution; dropouts reported Smoking: NR compression bandage # Work days missed: NR Withdrawals/dropouts ABI: NR Antibiotic Use: as needed adequately described: Wound location: leg Treatment Duration: 9 weeks None reported Wound type: venous Follow-up Duration: NR Wound size: NR Study Withdrawal (%): NR Wound grade: NR Treatment Compliance: NR Wound duration: 62% >1 mo Infection: excluded Comorbid conditions: 0% DM

119 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Donaghue 199817 Inclusion: >21 years of age; serum albumin N=75 Intervention (n=50): collagen- Allocation concealment: >2.5 grams/dl; adequate blood flow to lower Age (years): 59 alginate Unclear United States extremity (palpable pulses); foot ulceration of at Gender (% male): 72 Comparator (n=25): conventional Blinding: No Funding Source: least 1 cm2 Race/ethnicity: NR treatment with saline-moistened Industry BMI: NR Intention to treat analysis Exclusion: severe renal or liver impairment gauze Pre-albumin: 3.7 (ITT): Yes Therapy Type: (liver or creatinine tests 2 or more times higher HbA c (%): NR ALL: felted foam dressing with Collagen than normal); presence of any disorder that 1 Withdrawals/dropouts Smoking: NR window at site of ulcer; use of may interfere with ; evidence of adequately described: Yes # Work days missed: NR healing sandals; patient self osteomyelitis; clinical signs of infection; history ABI: NR dressing change as required of drug or alcohol abuse Wound location: foot Wound type: diabetic ulcer Antibiotic Use: NR Wound size: 2.7 cm2 Treatment Duration: 8 weeks Wound grade: Wagner I: 12%; II: 75%; Follow-up Duration: NR III: 13% Study Withdrawal (%): 19 Wound duration: 172 days Treatment Compliance: NR Infection: excluded Comorbid conditions (%): Diabetes: 100 Driver 200637 Inclusion: type 1 or 2 diabetes; age 18-95; ulcer N=40 (of 72 randomized) Intervention (n=40): platelet rich Allocation concealment: >4 weeks; HbA c <12%; index ulcer on plantar, Age (years): 57 plasma (AutoloGel); applied twice Adequate United States (14 1 medial, or lateral foot; area 0.5-20 cm2; Charcot Gender (% male): 80 weekly sites including VA Blinding: Yes (patients, deformity free of acute changes & undergone Race/ethnicity: Caucasian: 60; Hispanic: wound care clinics) Comparator (n=32): saline gel investigators, outcome structural consolidation; ulcer free of infection; 30; black: 7.5; other: 2.5 (Normlgel); applied twice weekly assessors) Funding Source: no bone, muscle, ligament, or tendon exposure; BMI: NR Industry ≥4 cm from any other wound; adequate Pre-albumin: NR Antibiotic Use: NR Intention to treat analysis perfusion HbA c (%): 7.9 Treatment Duration: 12 weeks (ITT): Yes but focused Therapy Type: 1 Smoking: NR Follow-up Duration: 3 months on per protocol analysis Platelet Rich Plasma Exclusion: investigational drug or device trial # Work days missed: NR Study Withdrawal (%): 44 due to protocol violations (30 days); ulcer size decrease ≥50% in 7 day ABI: NR Treatment Compliance: NR (n=24) and failure to run-in; non-diabetic ulcers; serum albumin Wound location (%): right foot: 60; left complete treatment (n=8) <2.5 g/dL; hemoglobin <10.5 mg/dL; radiation foot: 40; toe: 38; heel: 40 (NR for 9 or chemotherapy; renal dialysis; immune patients) Withdrawals/dropouts deficiency; known abnormal platelet activation Wound type: diabetic ulcer adequately described: Yes disorder; peripheral vascular repair in past Wound size: 3.5 cm2 30 days; known or suspected osteomyelitis; Wound grade: NR surgery required for healing; exposed tendon, Wound duration: NR ligaments, muscle, or bone; disorder that may Infection: excluded affect compliance; alcohol or drug abuse (past Comorbid conditions (%): year) Diabetes: 100

120 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Duzgun 200847 Inclusion: diabetic; ≥18 years; foot wound N=100 Intervention (n=50): HBOT Allocation concealment: present for ≥4 weeks despite appropriate Age (years): 61 administered at maximum working Inadequate “according Turkey local and systemic wound care; wounds were Gender (% male): HBOT 74%; pressure of 20 ATA; unichamber to a predetermined Funding Source: NR categorized according to a modification of Std Care 54%; p<0.05 pressure room; volume of 10m3 sequence wherein the Wagner classification; contraindication Race/ethnicity: NR at 2 to 3 ATA for 90 minutes + consecutively enrolled Therapy Type: to hyperbaric oxygen therapy (untreated BMI (>30, %): 63 (HBOT 80% standard therapy; treatment was 2 patients corresponding to Hyperbaric Oxygen pneumothorax, COPD, history of otic surgery, Std Care 46%; p<0.05) sessions/day, then 1 session on the an even random number (HBOT) upper respiratory tract infection, febrile state, Pre-albumin: NR following day received ST, and those history of idiopathic convulsion, hypoglycemia, HbA c (%): 8.4 corresponding to an odd 1 Comparator (n=50): standard current corticosteroid, amphetamine, Smoking: 56% random number received therapy catecholamine, or thyroid hormone use) # Work days missed: NR ST+HBOT” ABI: NR ALL: daily wound care (dressing Exclusion: none reported Blinding: None reported Wound location (%): foot changes, debridement); amputation Wound type: diabetic when indicated Intention to treat analysis Wound size, cm2: NR (ITT): Yes Wound grade (Wagner) (%): Antibiotic Use: as needed Grade II 18%; III 37%; IV 45% Treatment Duration: 20 to 30 days Withdrawals/dropouts Wound duration, months: NR Follow-up Duration: 92 weeks adequately described: Comorbid conditions (%): Study Withdrawal (%): None None reported History of DM: 100% reported History of HTN: 60% Treatment Compliance: NR History of hyperlipidemia: 58% Edmonds 200925 Inclusion: diabetes type 1 or 2; 18-80 years N=72 (of 82 randomized) Intervention (n=33): Apligraf (at Allocation concealment: old; primarily neuropathic origin, not infected; Age (years): 59 week 0 and weeks 4 and 8, if Adequate Europe, Australia present at least 2 weeks; surface area 1-16 Gender (% male): 86 needed) + Mepitel contact layer (multi-site) Blinding: No cm2; adequate vascular supply; able to follow Race/ethnicity (%): NR dressing Funding Source: NR treatment protocol (incl. off-loading) BMI: NR Intention to treat analysis Comparator (n=39): Mepitel HbA c (%): NR (ITT): No Therapy Type: Exclusion: active Charcot foot; non-neuropathic 1 Smoking: NR ALL: weekly debridement if Biological Skin origin; target ulcer with evidence of skin Withdrawals/dropouts # Work days missed: NR needed; saline-moist dressing; off- Equivalent cancer; osteomyelitis at any location requiring adequately described: Yes ABI: NR loading treatment; infected target ulcer; medical Wound location: plantar, forefoot condition which could impair healing; pregnant; Wound type: diabetic ulcer Antibiotic Use: NR corticosteroid use (current or prior); use of Wound size: 3.0 cm2 Treatment Duration: 12 weeks immunosuppressive agents; or Wound grade: NR Follow-up Duration: chemotherapy; prior treatment of study wound; Wound duration: 1.8 years 24 weeks post-treatment history of drug or alcohol abuse (in past year) Comorbid Conditions (%): Study Withdrawal (%): 12 Diabetes: 100 Treatment Compliance: NR

121 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Falanga 199854 Inclusion:18-85 years of age; ulcer due to N=275 (of 309 randomized) Intervention (n=146): human skin Allocation concealment: venous insufficiency (clinical signs/symptoms); Age (years): 60 equivalent (Apligraf) + elastic Adequate United States (15 no significant arterial insufficiency (ABI>0.65); Gender (% male): 52 wrap; applied up to 5 times in first sites) Blinding: No evidence of venous insufficiency (air Race/ethnicity(%): white 76; black 18; 3 wks (days 0, 3-5, 7, 14, and/or Funding Source: plethysmography or photo-plethysmography Asian 1; Hispanic 4 21) until estimated area of graft Intention to treat analysis Industry (refilling time <20 seconds) BMI: NR “take” >50%; compression alone (ITT): No

HbA1c (%): NR continued for total of 8 wks Therapy Type: Exclusion: clinical signs of cellulitis, vasculitis, Smoking: NR Withdrawals/dropouts Comparator (n=129): compression Biological Skin or collagen vascular disease; pregnancy or # Work days missed: NR adequately described: therapy reapplied weekly for 8 wks Equivalent lactation; uncontrolled diabetes; other impaired ABI: >0.65 per inclusion Partial – number of dropouts (n=72) is wound healing (renal, hepatic, hematologic, Wound location: NR Antibiotic Use: NR different than number not neurologic, or immunological disease); received Wound type: venous Treatment Duration: 8 weeks 2 included in data analysis corticosteroids, immunosuppressive agents, Wound size: 1.2 cm Follow-up Duration: 6 months (n=34) radiation therapy, or chemotherapy in past Wound duration: <6 months: 31%; 6-12 Study Withdrawal (%): unclear; month months: 21%; 1-2 years: 14%; >2 years: analysis of 275/309 (89%) 35% Treatment Compliance: NR Comorbid conditions (%): NR Falanga 199955 Inclusion: same as above with ulcer duration of N=120 for efficacy analysis Intervention (n=74): same as above Allocation concealment: See Falanga199854 >1 year (demographics from n=122; 2 Not applicable to subset Comparator (n=48): same as above extra in treatment group by “double United States (15 Blinding: No Exclusion: same as above randomization”) Antibiotic Use: NR sites) Age (years): 58 Treatment Duration: 8 weeks Intention to treat analysis Funding Source: Gender (% male): 61 Follow-up Duration: 6 months (ITT): No Industry Race/ethnicity (%): white 71; black 22; Study Withdrawal (%): NR for Withdrawals/dropouts Asian 0; Hispanic 6 subset of patients Therapy Type: 2 adequately described: No Wound size: 1.74 cm Treatment Compliance: NR Biological Skin Wound duration >1 year: 100% – number of dropouts in Equivalent Comorbid conditions (%): NR subset not reported Fumal 200279 Inclusion: at least 2 similar looking chronic leg N=17 patients (34 ulcers) Intervention (n=17 ulcers): 1% Allocation concealment: ulcers; minimal size 16 cm2; no evidence for Age (years): 55 silver sulfadiazine cream applied NR Belgium clinical infection 3x/week Blinding: No Funding Source: NR NOTE: no other patient characteristics Comparator (n=17 ulcers): Exclusion: neurological disorders; arterial reported Intention to treat analysis Therapy Type: Silver standard care occlusion; hypertension; diabetes; intake (ITT): Yes (no withdrawals Products of antibiotics or any other drug acting on ALL: saline rinse, hydrocolloid reported) microcirculation or blood coagulation dressing, compression bandage Withdrawals/dropouts Antibiotic Use: NR adequately described: Treatment Duration: 6 weeks None reported Follow-up Duration: none Study Withdrawal (%): NR Treatment Compliance: NR

122 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Gentzkow 199621 Inclusion: type 1 or 2 diabetes under reasonable N=50 Intervention: Dermagraft Allocation concealment: control; ulcers on plantar surface or heel; Age (years): 61 Group A (n=12): weekly (8 pieces & Adequate Pilot study for full-thickness defect >1 cm2; wound bed free Gender (% male): 70 8 applications) Naughton Blinding: No of necrotic debris/infection and suitable for Race/ethnicity (%): NR Group B (n=14): every 2 wks (8 United States (5 skin graft (no exposed tendon, bone, or joint; BMI: NR eight pieces & 4 applications) Intention to treat analysis

sites) no tunnels or sinus tracts that could not be HbA1c (%): 8.4 Group C (n=11): every 2 wks (4 (ITT): Yes debrided); adequate circulation (clinical signs Smoking: NR pieces & 4 applications) Funding Source: and ankle-arm index (AAI) >0.75); ability to # Work days missed: NR Withdrawals/dropouts Control Group D (n=13): standard Industry complete 12-week trial ABI: ankle-arm index 1.0 adequately described: No wound therapy Therapy Type: Wound location: plantar surface or heel Biological Skin Exclusion: >1 hospitalization during previous 6 Wound type: diabetic ulcer ALL: sharp debridement; saline- 2 Equivalent months due to hypoglycemia, hyperglycemia or Wound size: 2.4 cm moist gauze; off-loading ketoacidosis; ulcers of nondiabetic origin; use Wound grade: NR of medications known to interfere with healing Wound duration: 55.6 weeks Antibiotic Use: NR (e.g., corticosteroids, immunosuppressives, or Comorbid conditions (%): NR Treatment Duration: 12 weeks cytotoxic agents); pregnancy Follow-up Duration: mean 14 mos Study Withdrawal (%): NR Treatment Compliance: NR Hammarlund 199472 Inclusion: non-diabetic chronic (> 1 year N=16 Intervention (n=8): HBOT at 2.5 Allocation concealment: duration) leg ulcers; distal at Age (years, median): HBOT 71; control ATA for 90 minutes 5 days/week; Adequate Sweden ankle and first digit within normal range (≥100% 63 multi-place hyperbaric chamber; Blinding: Patients, Funding Source: NR and ≥70%, respectively, of upper arm blood Gender (% male): 50 pressurized for total of 30 sessions investigators pressure in mmHg) Race/ethnicity: NR over 6 weeks Therapy Type: BMI: NR Intention to treat analysis Hyperbaric Oxygen Comparator (n=8): placebo Exclusion: smoking; concomitant chronic Pre-albumin: NR (ITT): Yes (none) (hyperbaric air) (HBOT) conditions (e.g., diabetes, collagen disease); HbA c (%): NR 1 Withdrawals/dropouts large vessel disease; ulcers showing tendency Smoking: 0% (excluded) ALL: continued pre-study treatment to heal (by visual inspection) during 2 months # Work days missed: NR adequately described: Yes prior to study ABI: NR Antibiotic Use: NR (none) Wound location: leg Treatment Duration: 6 weeks Wound type: venous Follow-up Duration: 18 weeks (12 Wound size: 992 mm2 from week 6) Wound grade: NR Study Withdrawal: 0 Wound duration: NR but >1 yr Treatment Compliance: 100% Comorbid conditions (%): History of DM: 0%

123 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Hardikar 200529 Inclusion: type 1 or 2 diabetes; 18-80 years old; N=113 Intervention (n=55): 100ug rh- Allocation concealment: ≥1 full thickness chronic neuropathic ulcer of ≥4 Age (years): 55 PDGF (0.01%) gel applied daily Unclear India (8 sites) weeks duration; stage 3 or 4 (Wound, Ostomy Gender (% male): 70 with volume calculated based on Blinding: Unclear Funding Source: NR and Continence Nurses); infection controlled; Race/ethnicity (%): native of India: 100 ulcer size (reported to be double- area 1-40 cm2; adequate perfusion of foot BMI: NR Comparator (n=58): placebo gel blind but not specified) Therapy Type: (by ultrasonography, pulse, ABI, ankle or toe Pre-albumin: NR Platelet-derived applied daily pressure) HbA c (%): 7.5 Intention to treat analysis Growth Factor 1 Smoking: NR ALL: debridement, daily ulcer (ITT): No Exclusion: arterial venous ulcers; osteomyelitis # Work days missed: NR cleaning and dressing, off-loading or burn ulcers; poor nutritional status ABI: 1.06 Withdrawals/dropouts (total proteins <6.5 g/dL); uncontrolled Wound location: foot Antibiotic Use: appropriate use of adequately described: systemic antibiotics advised hyperglycemia (HbA1c>12%), persistent Wound type: diabetic Yes infection; life threatening concomitant Wound size: 12.8 cm2 Treatment Duration: 20 weeks diseases; foot deformities; chronic renal Wound grade: NR Follow-up Duration: NR insufficiency (sCr>3mg/dL); corticosteroid or Wound duration: 22.6 weeks Study Withdrawal (%): 18.6 immunosuppressant use; hypersensitivity to Comorbid conditions (%): Treatment Compliance: 97.3% (for gel components; childbearing age, pregnant or History of DM: 100 gel application, dressing changes, nursing without contraceptive use and off-loading) Harding 200560 Inclusion: age 30–85; clinical and documented N=194 (of 200 randomized) Intervention (n=95): LyphoDerm Allocation concealment: (refilling time <20 sec or duplex ultrasound Age (years): 67.5 (median) 0.9%; 8 applications (wks 0, 1, Unclear Multinational – in past 12 months) venous insufficiency; no Gender (% male): 39 2, 3, 4, 6, 8, 10) + standard care Belgium, United Blinding: No evidence of significant arterial insufficiency Race/ethnicity (%): white: 100 (dressing with hydrocolloid and Kingdom, Germany, (ABI>0.8); ulcer duration >6 wks not healed with BMI: 28.9 (median) compression therapy) Intention to treat analysis and Poland (21 sites) std care; size: 1-20 cm2 Pre-albumin: NR (ITT): No (excluded 6 Comparator (n=53): vehicle only + Funding Source: HbA c (%): NR patients who weren’t 1 standard care Industry Exclusion: arterial, decubitus, or diabetic Smoking: NR treated then one patient ulcer; cellulitis or vasculitis; condition that # Work days missed: NR Comparator (n=46): standard care from std care group with Therapy Type: impairs healing; systemic corticosteroids, ABI:1.1 (median) no baseline data); due Keratinocytes ALL: 4 week run-in period with immunosuppressive agents, radiation therapy, Wound location: leg (61% on medial to protocol violations, (LyphoDerm; alginate, hydrocolloid, foam, chemotherapy or surgical treatment/sclero- side) created an “as treated” freeze-dried lysate hydrogel dressings, or petrolatum therapy (past 3 months or planned); bed/ Wound type: venous leg ulcers ITT group (n=193) and a from cultured 2 gauze and compression therapy wheelchair-bound; clinically significant infected Wound size: 5.2 cm (median) PP group (n=167) allogeneic epidermal ulcer; consistently bleeding or excessively Wound grade: NR Antibiotic Use: NR keratinocytes) Withdrawals/dropouts exudating wound; exposed bone/tendon/fascia; Wound duration: 43 weeks (median) Study Duration: 28 wks (4 wk run adequately described: Yes treatment with - or growth factor-derived Comorbid conditions (%): in, 10 wk tx, 14 wk follow up) therapies (past month or planned); DVT; other History of DM: 6 (12/194) Study Withdrawal (%): 8.2 (16/194) clinical study (past month); allergic to study Treatment Compliance: 86.6% had materials; alcohol or drug abuse (past 5 years); no protocol deviation ulcer margin change >3 mm during 4 wk run-in

124 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Harding 201166 Inclusion: ≥18 years; male or female; ABI ≥0.8; N=281 Intervention (n=145): AQUACEL Ag Allocation concealment: venous leg ulcer (CEAP classification C6); Age (years): 70 (4 wks); AQUACEL (4 wks) Adequate Europe (43 sites) duration <24 months; size 5-40 cm2; ≥3 of the Gender (% male): 35 Comparator (n=136): Urgotul Silver Blinding: Unclear Funding Source: following: pain between dressing changes, Race/ethnicity: NR (4 wks); Urgotul (4 wks) Industry (reported perilesional skin erythema, edema, foul odor, or BMI: 30 Intention to treat analysis that sponsor high levels of exudate Pre-albumin: NR ALL: compression; dressing (ITT): Modified (had at

designed study and HbA1c (%): NR changes per clinical condition & least one exposure to approved final article; Exclusion: current antibiotics (week before Smoking: NR exudate; cleansing; mechanical treatment) authors had full inclusion); ulcers clinically infected or # Work days missed: NR debridement if needed Withdrawals/dropouts control over contents erysipelas; malignant; recent DVT or venous ABI: 1.04 Antibiotic Use: NR adequately described: Yes of article) surgery (past 3 months); progressive neoplastic Wound location: 2% foot, 47% ankle, lesion treated by radiotherapy or chemotherapy; 33% calf, 18% gaiter Treatment Duration: 8 weeks Therapy Type: Silver receiving immunosuppressive agents or high Wound type: venous Follow-up Duration: none Products dose corticosteroids Wound size: NR Study Withdrawal (%): 8% Wound grade: CEAP C6 AQUACEL; 12% Urgotul Wound duration: 0.76 yr Treatment Compliance: NR Comorbid conditions (%): NR Ieran 199070 Inclusion: skin lesions (ulcers due to idiopathic N=37 (of 44 randomized) Intervention (n=22): EMT stimulator Allocation concealment: chronic venous insufficiency or post-phlebitic Age (years): 66 (single pulse of electrical current Adequate Italy venous insufficiency) present at least for 3 Gender (% male): 38 generating a magnetic field of 2.8 Blinding: Patients, Funding Source: NR months Race/ethnicity: NR mT at a frequency of 75 Hz, with investigators BMI: NR, Obese 51% an impulse width of 1.3 ms for 3-4 Therapy Type: Exclusion: patients treated with steroids or Pre-albumin: NR hours daily) Intention to treat analysis Electromagnetic affected by systemic diseases; concomitant HbA c (%): NR (ITT): No 1 Comparator (n=22): sham EMT (EMT) arterial occlusive disease Smoking: NR Withdrawals/dropouts # Work days missed: NR ALL: no elastic compression ABI: NR adequately described: Yes Wound location: leg Antibiotic Use: as needed Wound type: venous Treatment Duration: 90 days or Wound size: <15 cm2 - EMT 54% (mean until wound healed 4.8), control 46% (5.0); >15 cm2 - EMT Follow-up Duration: at least one yr 36% (mean 34.2), control 64% (39.9) Study Withdrawal (%): 16% (n=7) Wound duration: 26 months Treatment Compliance: Average Comorbid conditions (%): stimulator use per day (hours) – History of DM: 19 intervention 3.8, control 3.7

125 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Jacobs 200839 Inclusion: Wagner grade 1 or 2 ulcerations N=40 Intervention (n=20): Bensal HP Allocation concealment: of the foot; ulcer size 3 cm diameter or less; Age (years): NR applied daily Unclear United States located on plantar aspect of foot; under care for Gender (% male): NR Comparator (n=20): SSC applied Blinding: Yes Funding Source: NR diabetes mellitus; demonstration of biphasic or Race/ethnicity: NR every 12 hours triphasic arterial sounds on arterial Doppler; ABI BMI: NR Intention to treat analysis Therapy Type: Silver of ≥0.75 Pre-albumin: NR ALL: debride; off-loading of weight (ITT): Yes Sulfadiazine Cream HbA c (%): ≤10% for inclusion bearing and shoe pressure (SSC) 1 Withdrawals/dropouts Exclusion: HbA1c greater than 10%; non- Smoking: NR palpable pulses or history of claudication or rest # Work days missed: NR Antibiotic Use: NR adequately described: Yes pain; clinical evidence of local sepsis (absence ABI: ≥0.75 for inclusion Treatment Duration: 6 weeks (none) of malodor, exudates, or erythema extending >1 Wound location: plantar Follow-up Duration: none cm from the ulceration) Wound type: diabetic ulcer Study Withdrawal (%): 0 Wound size: 3 cm diameter or less for Treatment Compliance: NR inclusion Wound grade: Wagner 1 or 2 Wound duration: NR Comorbid conditions (%): History of DM: 100 Jaiswal 201032 Inclusion: type I or type II diabetes and chronic N=50 Intervention (n=25): topical rhPDGF Allocation concealment: ulcers of at least 4 weeks duration; IAET stage Age (years): 53 gel (PLERMIN) applied once daily Adequate India III and IV Gender (% male): 84 Comparator (n=25): topical KY Jelly Blinding: Unclear Funding Source: NR Race/ethnicity: NR applied once daily Exclusion: ankle brachial pressure index (ABI) BMI: 22.4 Intention to treat analysis Therapy Type: <0.9 Pre-albumin: NR ALL: off-loading in patients with (ITT): Yes Platelet-derived HbA1c (%): NR plantar ulcers Growth Factors Smoking (%): 18 Withdrawals/dropouts # Work days missed: NR Antibiotic Use: NR adequately described: Yes ABI: NR Treatment Duration: 10 weeks Wound location: lower limb Follow-up Duration: NR Wound type: diabetic Study Withdrawal (%): NR Wound size: 28.2 cm2 Treatment Compliance: NR Wound grade: IAET class III – 62%; class IV – 38% Wound duration (median wks): Intervention 5; Control 6 Infection: NR Comorbid conditions (%): History of DM: 100 History of amputation or previous ulcer: 4% History of PVD: 0%

126 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Jørgensen 200577 Inclusion: chronic venous or mixed venous/ N=129 Intervention (n=65): sustained Allocation concealment: arterial leg ulcer with delayed healing process Age (years): 74 (median) release silver foam dressing Adequate Europe and North (area reduction of ≤0.5 cm in past 4 wks); ABI Gender (% male): 36 (Contreet Foam) America (7 countries, Blinding: No (open study) ≥0.65; compression therapy for 4 wks prior to Race/ethnicity: NR 15 sites) Comparator (n=64): foam dressing inclusion; ulcer size ≥2 cm2; max of 1.5 cm from BMI: NR Intention to treat without added silver (Allevyn Funding Source: edge of 10X10 cm dressing; at least 1 of Pre-albumin: NR analysis (ITT): For safety Hydrocellular) Industry a) increased exudate (past 4 wks), HbA1c (%): NR outcomes; per-protocol b) increased ulcer area pain (past 4 wks, per Smoking: NR ALL: compression therapy; analysis for performance Therapy Type: Silver patient), # Work days missed: NR dressing in place as long as outcomes Products c) discoloration of granulation tissue, ABI: 1.0 clinically possible (max=7 days) d) foul odor (per study personnel) Wound location: “leg” Withdrawals/dropouts Wound type: venous or mixed venous/ Antibiotic Use: Excluded adequately described: Yes Exclusion: clinical infection; current use of arterial Treatment Duration: 4 weeks antiseptics/antibiotics (1 wk prior to inclusion Wound size: 6.4 cm2 (median) Follow-up Duration: none Study Withdrawal (%): 15.5% & through study); HbA1c >10%, current Wound grade: NR systemic corticosteroids >10mg/d or other Wound duration: 1.05 years (median) Treatment Compliance: NR immunosuppressants from 4 wks prior to Comorbid conditions (%): NR inclusion; disease that may interfere with healing 40 Jude 2007 Inclusion: type 1 or 2 diabetes with HbA1c N=134 Intervention (n=67): sterile, non- Allocation concealment: ≤12%; serum creatinine ≤200 µmol/l; Grade 1 or Age (years): 60 woven sodium carboxymethyl- Adequate United Kingdom, 2 (Wagner) diabetic foot ulcer of non-ischemic Gender (% male): 74 cellulose primary ionic silver France, Germany, Blinding: No etiology Race/ethnicity: NR (AQAg, 1.2%) dressing; in place up Sweden (18 sites) BMI: NR to 7 days or as indicated Intention to treat analysis Funding Source: Exclusion: allergic to dressing components; Pre-albumin: NR (ITT): No (final wound Comparator (n=67): sterile, non- Industry known or suspected malignancy local to the HbA c (%): 8.0 evaluation for 65 of 67 in 1 woven calcium alginate (CA) study ulcer; taking systemic antibiotics >7 days Smoking: NR each group) dressing (moistened for use on dry Therapy Type: Silver prior to enrollment; inadequate arterial perfusion # Work days missed: NR wounds, changed daily on infected Products (dressing) (ABI<0.8, great toe SBP<40 mmHg, or forefoot ABI: 1.8 Withdrawals/dropouts wounds) adequately described: Yes TcPO2 <30 mmHg (supine) or <40 mmHg Wound location: 68% plantar; 32% non- (sitting)) plantar ALL: off-load of plantar ulcers Wound type: 75.5% neuropathic, 24.5% neuroischemic Antibiotic Use: at clinician’s Wound size: 3.7 cm2 discretion (15.5% at enrollment) Wound grade (%): Wagner I 75.5; Treatment Duration: 8 weeks or to Wagner II 24.5 healing Wound duration: 1.3 yrs Follow-up Duration: none Comorbid conditions (%): Study Withdrawal (%): 16 History of DM: 100% Treatment Compliance: NR

127 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Karatepe 201143 Inclusion: diabetic foot ulcer N=67 Intervention (n=30): Negative Allocation concealment: Age (years): 67.3 Pressure Wound Therapy (no Unclear Turkey Exclusion: none reported Gender (% male): 28 details provided) Blinding: No Funding Source: NR Race/ethnicity: NR Comparator (n=37): Standard BMI: NR Intention to treat Therapy Type: wound care (no details provided) Pre-albumin: NR analysis (ITT): Yes – no Negative Pressure HbA c (%): 85% poor control Antibiotic Use: NR withdrawals Wound Therapy 1 Smoking: NR Treatment Duration: NR Withdrawals/dropouts # Work days missed: NR Follow-up Duration: 1 month after adequately described: Yes ABI: 93% > 0.7 healing (mean of 4 months) – no withdrawals Wound location: foot Study Withdrawal (%): 0 Wound type: diabetic ulcer Treatment Compliance: NR Wound size: 32.4 cm2 Wound grade: NR Wound duration: 9.9 weeks Comorbid conditions (%): History of DM: 100 Kenkre 199671 Inclusion: venous ulcer with unsatisfactory N=19 Intervention 1 (n=5): EMT Allocation concealment: healing for at least the previous 4 weeks Age (years): 71 (Group 1 (59) (Elmedistraal) - 600 Hz electric field Unclear United Kingdom significantly younger than Group 2 (78) and 25 mT magnetic field Blinding: Patients, Funding Source: Exclusion: none reported & Comp. (73)) Intervention 2 (n=5): EMT investigators (reported as Industry Gender (% male): 26 (Elmedistraal) - 600 Hz electric field double-blind) Race/ethnicity: NR Therapy Type: days 1-5 and 800 Hz days 6-30, BMI: NR Intention to treat analysis Electromagnetic and 25 mT magnetic field Pre-albumin: NR (ITT): Yes (no dropouts) (EMT) HbA1c (%): NR Comparator (n=9): sham (placebo) Smoking: NR Withdrawals/dropouts # Work days missed: NR Antibiotic Use: NR adequately described: Yes ABI: NR Treatment Duration: 30 min week (no dropouts) Wound location: leg days for a total of 30 days Wound type: venous Follow-up Duration: 4-week Wound size: EMT 600 Hz: 63 mg (6 to observation period (dressing 269) EMT 800 Hz: 81 mg (46 to 197) changes only); final assessment on Control: 119 mg (35 to 526) day 50 Wound duration: 626 weeks Study Withdrawal (%): 0 Comorbid conditions (%): NR

128 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Kessler 200348 Inclusion: type 1 and type 2 diabetes; chronic N=27 (of 28 randomized) Intervention (n=15): HBOT; 2.5 Allocation concealment: foot ulcers (Wagner grades I, II, and III) Age (years): 64 ATA for two 90-min daily sessions Unclear France Gender (% male): 70 of 100% O breathing; multi-place 2 Blinding: Outcome Funding Source: Exclusion: gangrenous ulcers, severe Race/ethnicity: NR hyperbaric chamber pressurized; 5 assessors (surface area Foundation arteriopathy (TcPo2<30 mmHg), emphysema, BMI: 29.5 days/wk for 2 consecutive wks of the ulcer) proliferating retinopathy, claustrophobia Pre-albumin: NR Therapy Type: Comparator (n=13): Wound mgmt HbA c (%): 8.8 Intention to treat analysis Hyperbaric Oxygen 1 Smoking: NR ALL: multi-disciplinary wound (ITT): No, one withdrawal (HBOT) # Work days missed: NR management program (off-loading, not included in analysis ABI: NR metabolic control, antibiotics) Wound location: heel/sole 61%, toe Withdrawals/dropouts 39% Antibiotic Use: 63% adequately described: Yes Wound type: diabetic Treatment Duration: 2 weeks Wound size: 2.6 cm2 Follow-up Duration: 4 weeks Wound grade: Wagner I–III Study Withdrawal (%): 4% (n=1) Wound duration: ≥3 months Treatment Compliance: NR; Comorbid conditions (%): hospitalized for first 2 weeks History of CAD/CVD: 22 History of DM: 100 Krishnamoorthy Inclusion: full thickness venous leg ulcer without N=53 Intervention: compression and Allocation concealment: 200356 exposure of muscle, tendon or bone; venous Age (years): 69 Group 1 (n=13): 1 piece of Adequate reflux in of superficial or deep systems; Gender (% male): 42 Dermagraft applied weekly during Multinational (6 sites) Blinding: No ulcer duration ≥2 months but ≤ 60 months; size Race/ethnicity (%): Caucasian: 94; the first 11 weeks (12 applications) Funding Source: of 3-25 cm3; ABPI ≥ 0.7; < 50% healing from black: 4; Asian: 2 Group 2 (n=13): 1 piece of Intention to treat analysis Industry screening visit to day of first intervention (with BMI: 30.4 Dermagraft applied at day 0, weeks (ITT): Yes

use of multi-layer compression bandage during HbA1c (%): NR 1, 4 and 8 (4 applications) Therapy Type: 14 day screening period) Smoking: NR Group 3 (n=14): 1 piece of Withdrawals/dropouts Biological Skin # Work days missed: NR Dermagraft applied at day 0 adequately described: No Equivalent Exclusion: other causes of ulceration ABI: 1.1 Comparator (n=13): compression (rheumatoid vasculitis, diabetic foot ulcer); Wound location: leg therapy alone (Profore) severe leg edema (could not be controlled with Wound type: venous compression bandages); soft-tissue Wound size (median): 7.0 cm2 Wound Antibiotic Use: as needed that would interfere with wound healing; grade: NR Treatment Duration: 11 weeks impaired mobility; any underlying medical Wound duration (median): 47.7 days Follow-up Duration: NR condition (e.g., PVD, renal disease) Infection: NR Study Withdrawal (%): 11.3 Comorbid conditions (%): NR Treatment Compliance: NR

129 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Landsman 200820 Inclusion: ≥18 years, insulin or non-insulin N=26 Intervention (n=13): extracellular Allocation concealment: dependent diabetes; HbA c 5.5-12%; diabetic Age (years): 63 matrix (OASIS); max of 8 Adequate United States (4 1 ulcer; epidermal ulcers without exposed bone or Gender (% male): 69 applications sites) Blinding: No tendon; viable wound bed with granulated tissue Race/ethnicity: NR Comparator (n=13): living skin Funding Source: NR (bleeding following debridement), ulcer size BMI: NR Intention to treat analysis equivalent (Dermagraft); max of 3 1-16 cm2; present ≥4 weeks Pre-albumin: NR (ITT): Yes applications with reapplication at Therapy Type: HbA c (%): NR 1 2 and 4 wks if wound closure not Collagen Compared Exclusion: malnourished; allergic to porcine Smoking: NR Withdrawals/dropouts achieved with Biological Skin products; hypersensitivity to Dermagraft; severe # Work days missed: NR adequately described: No Equivalent arterial disease (ABI <0.9); radiation at ulcer ABI: NR ALL: debrided and cleansed; saline site; corticosteroids or immune suppressant Wound location: NR moistened gauze left in place for 1 use; immunocompromised; non-diabetic Wound type: diabetic ulcer wk; off-loading (boot) ulcer; vasculitis; severe rheumatoid arthritis; Wound size: 1.9 cm2 severe infection at wound site; osteomyelitis, Wound grade: NR Treatment Duration: 12 weeks necrosis, or avascular ulcer bed; ; Wound duration: NR Follow-up Duration: 8 weeks uncontrolled diabetes; active Charcot’s Comorbid conditions (%):NR Study Withdrawal (%): NR neuroarthropathy Treatment Compliance: NR

Lindgren 199858 Inclusion: out-patients; venous ulcers over N=27 Intervention (n=15): keratinocyte Allocation concealment: medial part of the distal third of the legs as Age (years): 76 (median) allograft + dressing (Mepitel) Unclear Sweden determined by clinical impression and ABI Gender (% male): 33.3 Comparator (n=12): dressing only Blinding: No Funding Source: (cutoff not given) Race/ethnicity: NR Industry BMI: NR ALL: CO2 laser debridement; if Intention to treat analysis Exclusion: none reported HbA1c (%): NR infection-free ≥1 wk then pneumatic (ITT): Unclear Therapy Type: Smoking: NR compression, treatment & elastic Biological Skin Withdrawals/dropouts # Work days missed: NR compression; inspected on day 3; Equivalent, adequately described: No ABI: 1.0 tx weekly; in bed for 24 hrs; feet Cryopreserved Wound type: venous elevated when sitting Wound size: 6.3 cm2 Wound duration: Antibiotic Use: as needed <2 years: 44.4% Treatment Duration: 8 weeks >2 years: 55.6% Follow-up Duration: 8 weeks Comorbid conditions (%): NR Study Withdrawal (%): 0% Treatment Compliance: NR

130 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Londahl 201046 Inclusion: diabetes; ≥1 full-thickness wound; N=94 Intervention (n=49): HBOT; ATA Allocation concealment: below ankle; >3 months; previously treated Age (years): 69 of 2.5; multi-place hyperbaric Unclear (“sealed Sweden at diabetes foot clinic for at least 2 months; Gender (% male): 81 chamber; compression of air for envelopes”) Funding Source: adequate distal perfusion or nonreconstructable Race/ethnicity: NR 5 minutes followed by 85-min Blinding: Patients, Foundation peripheral vascular disease BMI: NR daily (session duration 95 min); 5 investigators, outcome Pre-albumin: NR days/wk; 8 weeks (40 treatment assessments Therapy Type: HbA c(%): 7.9 sessions) Hyperbaric Oxygen Exclusion: contraindications for hyperbaric 1 Smoking: 25% current Intention to treat analysis (HBOT) treatment (severe obstructive pulmonary Comparator (n=45): placebo # Work days missed: NR (ITT): Yes disease, malignancy, and untreated (hyperbaric air); same schedule ABI: NR thyrotoxicosis); current drug or alcohol misuse; Withdrawals/dropouts Wound location (%): toe 40; plantar ALL: standard treatment at multi- vascular surgery in the lower limbs within the adequately described: Yes last two months; participation in another study; forefoot 26; middle 14; malleoli 6; heel disciplinary diabetes foot clinic suspected poor compliance 12; dorsal 1 (debride, off-load, treatment Wound type: diabetic of infection, revascularization, Wound size: 3.0 cm2 metabolic control) Wound grade (Wagner) (%): Grade II 26; III 56; IV 18 Antibiotic Use: Allowed Wound duration, months: 9.5 Treatment Duration: 8 weeks Comorbid conditions (%): Follow-up Duration: 1 year History of CAD/CVD: MI 29%; stroke Study Withdrawal (%): 20 (n=19) 16% Treatment Compliance: 57% History of DM: 100% attended 40 sessions; 80% History of amputation: 11% major; 39% attended >35 sessions; compliance minor with standard tx NR History of HTN: 75% History of hyperlipidemia: 88%

131 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Marston 200323 Inclusion: ≥18 years; type 1 or 2 diabetes; N=245 (ulcer duration >6wks) Intervention (n=130): Dermagraft; Allocation concealment: plantar forefoot or heel ulcer present ≥2 weeks; Age (years): 56 applied weekly up to 8 times over Unclear United States (35 1.0-20 cm2; full thickness but no exposed Gender (% male): 74 12 week study sites) Blinding: Yes muscle, tendon, bone, or joint capsule; no Race/ethnicity (%): Caucasian 72; Non- Comparator (n=115): standard Funding Source: necrotic debris; healthy vascularized tissue Caucasian 28 Intention to treat analysis wound care Industry present; ABI >0.7; adequate circulation to the BMI: NR (ITT): Yes foot (palpable pulse) HbA c (%): NR ALL: sharp debridement + saline- Therapy Type: 1 Withdrawals/dropouts Smoking: NR moistened gauze dressings; Biological Skin adequately described: No Exclusion: gangrene on affected foot; underlying # Work days missed: NR ambulatory with diabetic footwear Equivalent ABI: NR (>0.7 for inclusion) Charcot deformity; ulcer size changed (+ or Antibiotic Use: NR -) by >50% during 2 wk screening; severe Wound location: plantar forefoot (87%) or heel (13%) Treatment Duration: 12 weeks malnutrition (albumin <2.0); random blood sugar Follow-up Duration: 1 week follow- >450 mg/dl; urine ketones present; nearby Wound type: diabetic ulcers 2 up to confirm closure non-study ulcer; on systemic corticosteroids, Wound size: 2.4 cm Wound duration: 53 wks (41 wks vs. 67 Study Withdrawal (%): 19 immunosuppressive/cytotoxic agents; AIDS Treatment Compliance: NR or HIV-positive; at-risk for bleeding; cellulitis, wks, p=NR) osteomyelitis, or other infection Comorbid conditions (%): History of DM 100 McCallon 200044 Inclusion: diabetes; age 18-75 years; non- N=10 (pilot study) Intervention (n=5): continuous Allocation concealment: healing foot ulceration present >1 month Age (years): 52.8 pressure (125 mmHg) for 48 hrs; Inadequate United States Gender (% male): NR dressing change then intermittent Blinding: No Funding Source: NR Exclusion: venous disease; active infection not Race/ethnicity: NR pressure (125 mmHg); dressing BMI: NR change/assessment every 48 hrs Intention to treat Therapy Type: resolved by initial debridement; coagulopathy Pre-albumin: NR analysis (ITT): Yes – no Negative Pressure Comparator (n=5): saline HbA c (%): NR withdrawals 1 moistened gauze; changed every Wound Therapy Smoking: NR 12 hrs; assessed 3 times/wk # Work days missed: NR Withdrawals/dropouts adequately described: Yes ABI: NR ALL: initial surgical debridement; – no withdrawals Wound location: 9 forefoot, 1 midfoot bed rest or strict non-wt bearing Wound type: diabetic ulcer Wound size: NR Antibiotic Use: NR Wound grade: NR Treatment Duration: NR Wound duration: NR Follow-up Duration: Followed until Comorbid conditions (%): delayed primary closure or wound History of DM: 100 healed by secondary intention Study Withdrawal (%): 0 Treatment Compliance: NR

132 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Michaels 2009 a,b67,68 Inclusion: active ulceration of lower leg, present N=213 Intervention (n=107): silver- Allocation concealment: for more than 6 weeks Age (years): 71 donating dressings (list of 6 Adequate England (2 locations) Gender (% male): 46 approved for study) Blinding: No Funding Source: Race/ethnicity: NR Exclusion: insulin-controlled diabetes Comparator (n=106): non-silver Government BMI: NR Intention to treat analysis mellitus; pregnancy; sensitivity or specific dressings (any non-antimicrobial Pre-albumin: NR (ITT): No contraindications to the use of silver; ABI <0.8 low-adherence dressing) Therapy Type: Silver HbA c (%): NR Products in affected leg; maximum ulcer diameter <1 cm; 1 Withdrawals/dropouts Smoking: 18.3% ALL: multilayer compression atypical ulcers (e.g., suspicion of malignancy); adequately described: Yes coexisting skin conditions or vasculitis; receiving # Work days missed: NR bandage (per local practice); oral or parenteral antibiotic treatment ABI: NR dressings changed weekly unless Wound location: leg needed; other interventions used if Wound type: venous clinically appropriate Wound size: 72% <3 cm diam Wound grade: NR Antibiotic Use: NR Wound duration: 38.5% present for >12 Treatment Duration: 12 weeks weeks Follow-up Duration: to 1 year after Comorbid conditions (%): entry History of CAD/CVD: 14% history of MI Study Withdrawal (%): 2.3% or cardiac failure, 8% history of stroke Treatment Compliance: NR or TIA Miller 201078 Inclusion: lower leg ulcer; ABI ≥0.6; diameter N=266 (of 281 randomized) Intervention (n=140): Acticoat Allocation concealment: ≤15 cm; ≥18 years; no topical antiseptic Age (years): 80 (silver); clinician chose dressing Adequate Australia (2 sites) treatment in week before and no antibiotics 48 Gender (% male): 41 Comparator (n=141): Iodosorb Blinding: No – open label Funding Source hrs before recruitment; no systemic steroids; Race/ethnicity: NR (iodine); clinician chose dressing Foundation, no diagnosis of diabetes or malignancy related BMI: NR Intention to treat analysis Government to ulcer; not receiving palliative care; no known Pre-albumin: NR ALL: treated until signs of critical (ITT): No contraindications to treatment products; ≥ 1 HbA c (%): NR colonization and infection absent Therapy Type: Silver 1 Withdrawals/dropouts sign of infection or critical colonization (cellulitis, Smoking: NR 1 wk; non-antimicrobial dressing Products adequately described: Yes suppuration, lymphangitis, sepsis, bacteremia, # Work days missed: NR if no signs; required adherence to changes in granulation tissue, increased or ABI: NR compression bandaging malodorous exudate, new areas of slough or Wound location: lower leg 97% wound breakdown, impaired or delayed wound Wound type: venous (74%), mixed Antibiotic Use: 21% (55/266) healing, increased or new pain) (26.3%) Treatment Duration: 12 weeks Wound size: 705 mm2 Follow-up Duration: none Study Withdrawal (%): 5 Exclusion: none reported Wound grade: NR Wound duration: 54 weeks Treatment Compliance: Monitored Comorbid conditions (%): compression bandage adherence History of DM: 0

133 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Mostow 200553 Inclusion: chronic venous insufficiency (clinical N=120 Intervention (n=62): OASIS; each Allocation concealment: presentation, history) and/or positive venous Age (years): 64 week to non-epithelialized portion Adequate United States, United reflux; ≥18 years; ulcer >30 days; 1-49 cm2; Gender (% male): 42 Kingdom, Canada Comparator (n=58): standard Blinding: No between knee and ankle; full thickness and Race/ethnicity (%): white 81; black 16; (12 Sites) wound care non-healing; visible wound bed with granulation Asian 1; other 3 Intention to treat analysis Funding Source: tissue BMI: 31.9 ALL: weekly debride, dressing (ITT): Yes Industry HbA c (%): NR changes; non-adherent dressing + 1 Withdrawals/dropouts Smoking: NR 4 layer compression bandaging Therapy Type: Exclusion: infected, necrotic, or avascular ulcer adequately described: Yes bed; cellulitis, osteomyelitis, or exposed bone/ # Work days missed: NR Biological Dressings ABI: NR, all >0.8 by exclusion Antibiotic Use: NR tendon/fascia; severe RA; uncontrolled CHF Treatment Duration: 12 weeks; or diabetes (HbA c >12%); ABI <0.8; history Wound type: venous 1 2 control group offered cross-over of local radiation; corticosteroids or immune Wound size: 11.1 cm Wound duration: 1-3 months: 34.2%; to OASIS if not healed; treated for suppressives; known or hypersensitivity 4 weeks; continued for total of 12 to products; sickle cell disease; hemodialysis; 4-6 months: 15.8%; 7-12 months: 10.0%; >12 months: 36.7%; not weeks if initial improvement seen malnutrition (albumin <2.5 g/dL); investigational Follow-up Duration: 6 months; drug or device treatment in last 30 days specified: 3.3% Comorbid conditions (%): NR (retained 45% of ITT population) Study Withdrawal (%): 20 Treatment Compliance: NR Naughton 199722 Inclusion: diabetes; neuropathic full-thickness N=235 (of 281 randomized) Intervention (n=109): Dermagraft; Allocation concealment: plantar surface foot ulcers of the forefoot or Age (years): NR day 0 and weeks 1-7 (8 total) Unclear United States (20 heel; ulcer size >1.0 cm2 Gender (% male): NR sites) Comparator (n=126): standard Blinding: “Single-blinded” Race/ethnicity (%): NR wound care Funding Source: Exclusion: initial rapid healing in response to BMI: NR Intention to treat analysis Industry standard care during a screening period HbA1c (%): NR ALL: debridement, infection control, (ITT): No Smoking: NR saline-moistened gauze dressings, Therapy Type: Withdrawals/dropouts # Work days missed: NR and off-weighting Biological Skin ABI: NR adequately described: No Equivalent – Wound location: plantar forefoot or heel Antibiotic Use: NR Dermagraft Wound type: Diabetic ulcer Treatment Duration: 12 weeks (8 Wound size: NR week intervention) Wound duration: NR Follow-up Duration: to 32 weeks Comorbid conditions (%): Study Withdrawal (%): 16.4 History of DM: 100 Treatment Compliance: NR

134 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Navratilova 200459 Inclusion: venous ulcer diagnosed by N=50 Intervention (n=25): single Allocation concealment: history, , and Doppler Age (years): 63 application of cryopreserved No Czech Republic ultrasonography Gender (% male): 36 cultured epidermal keratinocytes; Blinding: No Funding Source: Race/ethnicity: NR nonadherent silicone dressing Government Exclusion: arterial ulcer; ulcer size <2 cm2; BMI: 30.1 and gauze bandages; dressings Intention to treat analysis HbA c (%): NR removed after 5 days then (ITT): Yes Therapy Type: duration <3months; uncompensated diabetes 1 mellitus; pronounced anemia (hg <10.0g/dL); Smoking: NR changed every 3 days Biological Skin # Work days missed: NR Withdrawals/dropouts uncompensated heart insufficiency; pronounced Comparator (n=25): same except Equivalent, ABI: NR, >0.8 per exclusion adequately described: hypoproteinemia (albumin <3.5g/dL); ABI allografts of lyophilized cultured cryopreserved Wound location: leg None reported versus lyophilized <0.8; metastatic malignant tumor; systemic epidermal keratinocytes immunosuppressive therapy Wound type: venous ulcer allografts 2 Wound size: 10.7 cm (cryopreserved ALL: debride and dressings until 12.4 cm2, lyophilized 9.0 cm2) clean & granulating wound base Wound duration: 23.7 months achieved; wet saline dressings 1-3 (cryopreserved 21 months, lyophilized days before graft; hospitalized for 17 months) graft; bed rest and limb elevation Comorbid conditions (%): NR for 48 h after grafting Antibiotic Use: systemic; 1 day before allografts if infection Treatment Duration: single application Follow-up Duration: 3 months Study Withdrawal (%): 0% Treatment Compliance: NR

135 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Niezgoda 200519 Inclusion: ≥18 years; type 1 or 2 diabetes; non- N=73 (of 98 randomized) Intervention (n=37): OASIS; saline Allocation concealment: healing diabetic ulcer of >30 days; ulcer full Age (years): 58 and secondary dressing; re- Adequate United States and thickness with size of 1-49 cm2; visible wound Gender (% male): 60 applied weekly as needed Canada (9 Sites) Blinding: Unclear bed with granulation tissue; Grade I, Stage A Race/ethnicity %: NR Comparator (n=36): PDGF Funding Source: (UT classification) BMI: 32.5 Intention to treat analysis (becaplermin/Regranex); patients Industry (provided Pre-albumin: NR (ITT): No applied daily; saline-moistened study supplies) HbA c (%): 8.3 Exclusion: ulcer of non-diabetic etiology; 1 gauze dressing for 12 hrs then Smoking: NR Withdrawals/dropouts uncontrolled diabetes ( A1C >12%); rinsed and covered Therapy Type: # Work days missed: NR adequately described: Biological Dressings documented severe arterial disease or low Yes ABI: NR ALL: off-loading; clean and debride Compared to blood supply (TcPO2 <30 mmHg or toe-brachial Wound location: 65% plantar weekly Platelet-derived index <0.70); on corticosteroids or immune suppressives; infected, necrotic, or avascular Wound type: diabetic ulcer Growth Factors Wound size: 4.1 cm2 Antibiotic Use: NR ulcer bed; cellulitis, osteomyelitis, or exposed Treatment Duration: 12 weeks; if bone/tendon/fascia; active Charcot or sickle cell Wound duration (%): 1-3 months: 49; 4-6 months: 16; 7-12 months: 15 >12 not healed, crossover tx offered; disease; hemodialysis, malnutrition (albumin treated for 4 weeks; continued <2.5 g/dL); known allergy/hypersensitivity months: 19 Comorbid conditions (%): for total of 12 weeks if initial to products; treatment with any other improvement seen investigational drug or device (past 30 days) History of DM: 100% Type 1 - 49% OASIS, 22% PDGF Follow-up Duration: 6 months (only Type 2 - 51% OASIS, 78% PDGF 50% of per protocol sample) History of PVD: 0% severe Study Withdrawal (%): 26 Treatment Compliance: NR Omar 200457 Inclusion: chronic venous leg ulcers (based on N=18 Intervention (n=10): Dermagraft at Allocation concealment: clinical examination, duplex finding of venous Age (years): 60 weeks 0, 1, 4 & 8 Unclear (“computer- United Kingdom dysfunction [all had evidence of superficial Gender (% male): 61 generated code based on Comparator (n=8): non-adherent Funding Source: reflux, but no deep venous reflux or DVT]; and Race/ethnicity: NR the order of admittance to dressing Unclear (“statistical exclusion of other causes [especially arterial BMI: NR the study”) advice and insufficiency, ABPI >0.9]); duration >12 wks; HbA c (%): NR ALL: cleaning, debridement, four- 1 Blinding: Yes (ulcer guidance” from ulcer area 3–25 cm2, clean ulcer bed with Smoking: NR layer compression bandaging measurement) industry) healthy granulation tissue # Work days missed: NR Antibiotic Use: NR ABI: 1.06 Intention to treat analysis Therapy Type: Treatment Duration: 12 weeks Exclusion: none reported Wound type: venous leg ulcer (ITT): Unclear Biological Skin Wound size: 10.7 cm2 Follow-up Duration: none Equivalent, Wound duration: 119.3 weeks Study Withdrawal (%): NR Withdrawals/dropouts Dermagraft Comorbid conditions (%): NR Treatment Compliance: NR adequately described: None reported

136 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Reyzelman 200918 Inclusion: ≥18 years; type 1 or 2 diabetes; N=85 (of 86 randomized) Intervention (n=47): single Allocation concealment: diabetic foot ulcer; 1-25 cm2; absence of Age (years): 57 application - 4x4 cm Unclear United States (11 infection; adequate circulation to affected Gender (% male): NR human acellular dermal sites) Blinding: No extremity (TcPO2 >30 mmHg, ABI 0.70–1.2, or Race/ethnicity (%): NR regenerative tissue matrix graft Funding biphasic Doppler waveforms in arteries of lower BMI: 33.8 (based on n=83) (GRAFTJACKET); sutured or Intention to treat analysis

Source: Industry extremity) HbA1c (%): 7.9 stapled in place; silver-based (ITT): Yes (included all (compensation to Smoking: NR non-adherent dressing (Silverlon) but one intervention study personnel and # Work days missed: NR applied; secondary dressings as group patient who Exclusion: poor glycemic control (HbA1c >12%); consultants involved serum Cr >3.0 mg/dl; sensitivity to antibiotics ABI: NR determined by investigator was removed from in data interpretation Wound location (%): toe 28; foot 44; participation due to non- used in preparation of cellular matrix; non Comparator (n=39): standard and writing; therapy heel 17; other 11 compliance) revascularable surgical sites; ulcers probing to care (moist-wound therapy with provided at no bone; wound recently treated with biomedical Wound type: diabetic ulcer 2 alginates, foams, hydrocolloids Withdrawals/dropouts charge) Wound size: 4.3 cm or topical growth factors or hydrogels at discretion of Wound duration: 23.1 weeks adequately described: physician); dressing changes daily Therapy Type: (Note: range=0-139 weeks) Yes or per treating physician Collagen Comorbid conditions (%): History of DM: 100; Type 1 – 8.2; Type ALL: surgical site prep. before tx; 2 – 91.8 off-load (removable cast walker) Antibiotic Use: if infection present Treatment Duration: 12 weeks Follow-up Duration: none Study Withdrawal (%): 8% Treatment Compliance: NR Romanelli 200775 Inclusion: >18 years; mixed A/V leg ulcer by N=54 Intervention (n=27): OASIS Allocation concealment: clinical and instrumental assessment; venous Age (years): 63 Inadequate (every other Italy Comparator (n=27): Hyaloskin reflux by Doppler flow studies; ABPI >0.6 and Gender (% male): 48 patient that was selected Funding Source: <0.8; ulcer duration >6 weeks; 2.5-10 cm2; Race/ethnicity (%): NR ALL: saline + secondary dressing; by clinician for study) Industry >50% granulation tissue on wound bed BMI: NR no compression; observed 2x/wk; Blinding: No HbA c (%): NR (DM excluded) dressing change as needed (approx. Therapy Type: 1 Smoking: 0 (excluded) 1x/wk); all dressings applied in clinic Intention to treat analysis Biological Dressing Exclusion: diabetes; current smoker; ABPI <0.6; clinical signs of wound infection; necrotic tissue # Work days missed: NR (ITT): No ABI: 0.6 to 0.8 Antibiotic Use: NR on wound bed; known allergy to treatment Treatment Duration: 16 weeks Withdrawals/dropouts products; unable to follow protocol Wound type: mixed A/V ulcers Wound size: 6 cm2 Follow-up Duration: none adequately described: Wound duration: 7.8 weeks Study Withdrawal (%): 7.4 (4/54) Yes Comorbid conditions (%): Treatment Compliance: NR History of DM: 0 History of PVD: 100

137 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Romanelli 201076 Inclusion: venous or mixed A/V leg ulcer; ABI N=50 Intervention (n=25): OASIS Allocation concealment: 0.6-0.8; duration >6 months; size >2.5 cm2; Age (years): NR Unclear Italy Comparator (n=25): petroleum- 50% granulation tissue on wound bed Gender (% male): 48 impregnated gauze Blinding: Unclear Funding Source: Race/ethnicity (%): NR Industry Exclusion: clinical signs of infection; ABI <0.6; BMI: NR ALL: moistened with saline + Intention to treat analysis HbA c (%): NR secondary nonadherent dressing; (ITT): No Therapy Type: necrotic tissue on wound bed; known allergy to 1 Smoking: NR assessed weekly for up to 8 wks; Biological dressing treatment products; unable to follow protocol Withdrawals/dropouts # Work days missed: NR patients changed secondary adequately described: ABI: NR but for inclusion 0.6-0.8 dressing at home Wound location: leg Yes Wound type: venous or mixed A/V ulcer Antibiotic Use: NR Wound size: 24.4 cm2 Treatment Duration: 8 weeks Wound duration: 7.1 weeks Follow-up Duration: stated monthly Comorbid conditions (%): NR follow-up for 6 months (results not reported) Study Withdrawal (%): 4% (2/50) Treatment Compliance: NR Saad Setta 201136 Inclusion: age 40-60 yrs; type 1 or 2 diabetes; N=24 Intervention (n=12): platelet rich Allocation concealment: normal peripheral platelet count (>150,000 Age (years): NR plasma applied twice weekly Unclear Egypt mm3) Gender (% male): NR (intervals of 3-4 days) Blinding: No Funding Sources: Race/ethnicity: NR Comparator (n=12): platelet poor NR BMI: NR Intention to treat analysis Exclusion: receiving or had received chemo or plasma (same schedule) Pre-albumin: NR (ITT): Unclear Therapy Type: radiation therapy in past 3 months; screening HbA c (%): NR ALL: off-loading of ulcer area Platelet Rich Plasma serum albumin <2.5 ml/dl or hemoglobin <10.5 1 Withdrawals/dropouts mg/dl or platelet count <100x109/l; peripheral Smoking: 33.3% # Work days missed: NR Antibiotic Use: NR adequately described: No vascular disease; bacteria count (study ulcer) Treatment Duration: 20 weeks (not reported) 5 ABI: NR >10 organisms/gram tissue;, exposed tendons, Follow-up Duration: none ligaments or bone Wound location: foot Wound type: diabetic Study Withdrawal (%): NR Wound size: 9.4 cm2 Treatment Compliance: NR Wound grade: NR Wound duration: ≥12 weeks Infection: NR Comorbid conditions (%): History of HTN: 70

138 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Schuler 199669 Inclusion: age >18 years old; ulcers <50 cm2; N=54 Intervention (n=28): below-knee Allocation concealment: ulcers <2 years old Age (years): 57 gradient compression elastic Unclear United States Gender (% male): 46 stocking + external pneumatic Blinding: No Funding Source: Exclusion: ABI <0.9; cancer; massive leg Race/ethnicity: NR compression; applied daily (1 hour Industry edema due to congestive heart failure; cellulitis; BMI: 33 in morning + 2 hours in evening) Intention to treat analysis Pre-albumin: NR (ITT): No osteomyelitis; sickle cell disease; use of Comparator (n=26): Unna’s boot Therapy Type: HbA c (%): NR Intermittent steroids or vasoconstrictive medications; DVT 1 Withdrawals/dropouts or pulmonary embolism in previous 6 months; Smoking (%): 31 ALL: leg elevation 2X/day Pneumatic # Work days missed: NR adequately described: Compression ligation or injection in Antibiotic Use: NR Yes previous year ABI: 1.1 Wound location: NR Treatment Duration: 6 months Wound type: venous ulcer Follow-up Duration: NR Wound size: 9.9 cm2 Study Withdrawal (%): 13 Wound grade: NR Treatment Compliance: 93% (4 Wound duration: 306 days total dropped for non-compliance) Comorbid conditions (%): NR Stacey 200062 Inclusion: venous ulceration based on ABI >0.9, N=86 Intervention (n=42): bandage Allocation concealment: venous refilling time < 25 seconds, blood tests Age (years): 71 soaked in platelet lysate in Adequate Australia negative for other causes of ulceration Gender (% male): 42 phosphate buffered saline (PBS) Blinding: Unclear Funding Source: Race/ethnicity: NR Comparator (n=44): placebo (PBS) Government, BMI: NR Intention to treat analysis Exclusion: none reported soaked bandage Industry Pre-albumin: NR (ITT): Unclear HbA c (%): NR ALL: compression bandaging; Therapy Type: 1 Withdrawals/dropouts Smoking: NR dressings/bandages applied twice Platelet Rich Plasma adequately described: # Work days missed: NR weekly ABI: NR Yes Wound location: leg Antibiotic Use: NR Wound type: venous ulcer Treatment Duration: 9 months Wound size: 4.9 cm2 Follow-up Duration: NR Wound grade: NR Study Withdrawal (%): 9 Wound duration: 12 weeks Treatment Compliance: NR Comorbid conditions (%): NR

139 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Steed 1995, 200633,34 Inclusion: ≥19 years; ulcer area 1-100 cm2; N=118 Intervention (n=61): platelet- Allocation concealment: chronic (≥8 weeks duration) non-healing; full- Age (years): 61 derived growth factor (PDGF-BB Adequate United States thickness; lower extremity ulcer resulting from Gender (% male): 75 100ug/g gel) applied once/day by Blinding: Unclear Funding Source: diabetes; free of infection; adequate arterial Race/ethnicity (%): white: 86; other: 14 patient or patient caregiver Industry (responsible blood supply BMI: NR Intention to treat analysis Comparator (n=57): placebo gel for conduct of trial Pre-albumin: NR (ITT): Yes applied as above and all analyses) HbA c (%): NR Exclusion: nursing, pregnant, or of childbearing 1 Withdrawals/dropouts Smoking: NR ALL: debridement as needed; Therapy Type: potential; hypersensitivity to study gel; >3 adequately described: # Work days missed: NR instructed on off-loading Platelet-derived ulcers; ulcers from large-vessel arterial Yes ischemia, venous insufficiency, pressure, ABI: NR Growth Factors Wound location: foot Antibiotic Use: NR or necrobiosis lipoidica diabeticorum; Treatment Duration: 20 weeks osteomyelitis; malignant or terminal disease; Wound type: diabetic ulcer Wound size: 7.2 cm2 Follow-up Duration: NR alcohol or substance abuse; thermal, electrical, Study Withdrawal (%): 27 or wounds at site of target ulcer; Wound grade: NR Wound duration: 78 weeks Treatment Compliance: 98% receiving corticosteroids, immunosuppressive (weight of gel tube, diary of agents, radiation therapy, or chemotherapy Infection: NR Infection: Excluded dressing changes) Comorbid conditions (%): NR

140 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Vanscheidt 200761 Inclusion: age 18-90; chronic venous leg ulcers N=225 Intervention (n=116): 2 wks before Allocation concealment: (>3-month duration); area 2-50 cm2 after sharp Age (years): 67 Day 0 – skin biopsy to collect and Unclear Europe (Hungary, debridement (±5%); venous insufficiency (by Gender (% male): 37 cultivate autologous keratinocytes Czech Republic, Blinding: No Doppler sonography with reflux in superficial Race/ethnicity: NR Day 0 – debride, disinfect & rinse; Germany) and/or deep veins, venous refilling time <20 BMI: 28.6 applied autologous keratinocytes Intention to treat analysis Funding Source: NR seconds, duplex sonography, or phlebography); Pre-albumin: NR within fibrin sealant; pressure (ITT): Yes

ulcer located below knee joint excluding ulcers HbA1c (%): NR dressing; compression therapy; Therapy Type: of distal metatarsal area Smoking: 19.1% repeated up to 3X in first 3 mos; Withdrawals/dropouts Keratinocytes # Work days missed: NR further applications allowed if >2 adequately described: No (autologous ABI: NR, but all >0.8 by criteria wks apart; compression therapy keratinocytes Exclusion: not able to get/apply compression therapy; ABI <0.8; vasculitis, severe rheumatoid Wound location: below knee maintained throughout 6 months combined with fibrin Wound type: venous leg arthritis, or other connective tissue diseases; Comparator (n=109): Day 0 – sealant: BioSeed-S) Wound size: previous surgery on venous system or Same except non-adherent gauze; 2-10 cm2: 60.4% (136/225) sclerotherapy, phlebitis, or DVT in past 3 continuous compression therapy; >10 cm2: 38.7% (87/225) months; significant medical conditions that sharp debridement and paraffin Wound grade: NR impair wound healing (e.g., renal and hepatic gauze as needed insufficiency or uncontrolled diabetes); known Wound duration: hypersensitivity to bovine proteins or other 3-12 months: 59.1%(133/225) ALL: debrided, routine dressings constituents of BioSeed-S (if randomized to >12 months: 40.9% (92/225) and compression for 4 weeks that group); pregnant or breast-feeding women, Comorbid conditions (%): NR prior to Day 0 (not randomized if or of childbearing age not using contraception responsive to std care after 2 wks) during treatment phase Antibiotic Use: NR Treatment Duration: up to 3 mos Follow-up Duration: 6 mos Study Withdrawal (%): NR Treatment Compliance: NR

141 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Veves 200124 Inclusion: type 1 or 2 diabetes; age 18-80 N=208 (of 277 randomized) Intervention (n=112): Graftskin Allocation concealment: years; HbA c 6-12%; full thickness neuropathic Age (years): 57 (Apligraft); at baseline then weekly, Adequate- United States (24 1 ulcers ≥2 weeks in duration (excluded dorsum Gender (% male): 78 if needed, for maximum of 4 weeks sites) Blinding: No of foot and calcaneous); ulcer size 1-16 cm2; Race/ethnicity: white: 69; African (max of 5 application) Funding Source: dorsalis pedis and posterior tibial pulses American: 16; Hispanic: 13 Intention to treat analysis Comparator (n=96): saline Industry audible by Doppler BMI: 32 (ITT): Modified (excluded moistened gauze HbA c (%): 8.6 69 patients during 1 week Therapy Type: 1 Smoking: NR ALL: scheduled dressing changes; run-in) Biological Skin Exclusion: clinical infection at ulcer site; Alcohol: NR off-loading Equivalent significant lower extremity ischemia; active Withdrawals/dropouts Charcot’s disease; ulcer of non-diabetic # Work days missed: NR ABI: >1.0 54%; <0.8 10% Antibiotic Use: NR adequately described: pathophysiology; significant medical conditions Treatment Duration: maximum of Yes that would impair healing Wound Type: neuropathic diabetic foot ulcer 4 weeks Wound size: 2.9 cm2 Follow-up Duration: 12 weeks with Wound Duration: 11.3 months safety evaluation to 3 months Comorbid Conditions (%): NR Study Withdrawal (%): 21 Treatment Compliance: 98% Veves 200216 Inclusion: ≥18 years of age; diabetic foot ulcer; N=276 Intervention (n=138): collagen & Allocation concealment: ≥30 days duration; Wagner grade 1 or 2; area Age (years): 58.5 oxidized regenerated cellulose Unclear United States ≥1 cm3; adequate circulation Gender (% male): 74 dressing (Promogran); application Blinding: No (11 sites) Race/ethnicity (%): white 63, African frequency at clinicians’ discretion American 10; Hispanic 16; Native Intention to treat analysis Funding Source: Exclusion: clinical signs of infection; exposed Comparator (n=138): isotonic American 12 (ITT): Yes bone; concurrent condition that may interfere sodium chloride solution- Industry BMI: NR with healing; known alcohol or drug abuse; moistened gauze Withdrawals/dropouts Therapy Type: Pre-albumin: NR dialysis; corticosteroids; immunosuppressive adequately described: Collagen HbA1c (%): 8.6 ALL: surgical debridement at all agents; radiation or chemotherapy; Yes hypersensitivity to dressing components; Smoking: NR study visits; dressing changes inability to be fitted with off-loading device; # Work days missed: NR according to good clinical practice; multiple ulcers on same foot ABI: NR off-loading Wound location: foot Wound type: diabetic ulcer Antibiotic Use: NR Wound size: 2.8 cm2 Treatment Duration: 12 weeks Wound grade: NR Follow-up Duration: NR Wound duration: 3 months (median) Study Withdrawal (%): 32 Infection: NR Treatment Compliance: >90% Comorbid conditions (%): NR (both groups; tx, dressing change)

142 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Vin 200252 Inclusion: venous leg ulcers; free of infection; N=73 Intervention (n=37): Promogran Allocation concealment: ≥30 days duration; ABPI ≥0.8; 2 cm-10 cm in Age (years): 73 dressing + Adaptec (petrolatum- Unclear France (14 sites) any one dimension(if multiple ulcers largest Gender (% male): 35 impregnated dressing) Blinding: Partial Funding Source: was selected if ≥3 cm away from any other Race/ethnicity: NR Comparator (n=36): Adaptec only (investigator assessment Industry ulcer) BMI: 28 validated by 2 clinicians) Pre-albumin: NR ALL: compression bandages; Therapy Type: HbA c (%): NR dressing changes 2x/wk or more Intention to treat analysis Collagen Exclusion: unwilling to wear compression 1 bandage continuously; immobile and unable Smoking (%): 8 (ITT): Yes # Work days missed: NR Antibiotic Use: NR to care for themselves; medical condition that Treatment Duration: to 12 weeks Withdrawals/dropouts may interfere with healing including carcinoma, ABI: 1.1 Wound location: leg Follow-up Duration (mean): adequately described: vasculitis, connective tissue disease, and Promogran=65.9 days Yes disorders; received topical Wound type: venous ulcer 2 Adaptec=63.8 days corticosteroids, immunosuppressive agents, Wound size: 8.2 cm Wound grade: NR Study Withdrawal (%): 26 radiation therapy, or chemotherapy in 30 days Treatment Compliance: NR before study entry Wound duration: 9.2 months Comorbid conditions (%): History of CAD: 11; History of DM: 14; History of HTN: 49 Viswanathan 201141 Inclusion: type 2 diabetes; Wagner Grade I, II, N=38 (of 40 randomized) Intervention (n=20): diabetic Allocation concealment: or III ulcer Age (years): 59 wound cream (polyherbal Unclear India Gender (% male): NR formulation) Blinding: Unclear Funding Source: Race/ethnicity: NR Exclusion: clinical signs of severe infection; Comparator (n=20): silver Industry Pre-albumin: NR Intention to treat analysis: exposed bone; unwilling to participate in study sulphadiazine cream HbA c (%): 10.7 No Therapy Type: Silver 1 Smoking: NR ALL: daily dressing changes Products Withdrawals/dropouts # Work days missed: NR (saline wash, cream applied) ABI: NR adequately described: Wound location: plantar (66% fore, 24% Antibiotic Use: If ulcers showed Yes mid, 11% hind) clinical signs of infection Wound type: diabetic ulcer Treatment Duration: unclear Wound size: 4.6 X 3.3 cm Follow-up Duration: 5 months Wound grade: 29.0% I, 31.6% II, 39.5% Study Withdrawal (%): 5 III Treatment Compliance: NR Wound duration: 14.5 days Comorbid conditions (%): History of DM: 100 History of PAD: 23.7

143 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Vuerstack 200680 Inclusion: hospitalized with chronic N=60 Intervention (n=30; 28 received Allocation concealment: venous, combined venous and arterial, or Age (years): 72 (median) tx): vacuum-assisted; permanent Adequate Netherlands (2 sites) microangiopathic leg ulcers (>6 months Gender (% male): 23 negative pressure (125 mmHg) Blinding: No Funding Source: duration); ambulatory; failed conservative local Race/ethnicity: NR until skin graft + 4 days after graft Industry (no treatment for ≥6 months BMI: NR Intention to treat analysis Comparator (n=30; 26 received influence on data Pre-albumin: NR (ITT): Unclear (ITT tx): daily local wound care and analysis, data HbA c (%): NR for adverse events Exclusion: age >85 years; use of immune 1 compression therapy until skin interpretation, Smoking: 26% but unclear for other suppression; allergy to wound therapies; graft; standard care after graft writing of report, malignant or vasculitis origin; ABI <0.6 # Work days missed: NR outcomes) or manuscript ABI: 100 (median) ALL: initial necrosectomy; full- Withdrawals/dropouts submission) Wound location: leg thickness punch skin graft when adequately described: Wound type: venous (43%), combined 100% granulation tissue on surface Therapy Type: Yes arterial/venous (13%), arteriolosclerotic and wound secretion minimal; only Negative Pressure (46%) toilet and basic hygiene mobility Wound Therapy 2 Wound size: 38 cm during treatment Wound grade: NR Wound duration: 7.5 months Antibiotic Use: 3.5% at baseline Comorbid conditions (%): Treatment Duration: to closure History of DM: 17% (type 2) Follow-up Duration: 12 months History of HTN: 43% Study Withdrawal (%): 10 Immobility: 42% Treatment Compliance: Inpatients

144 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Wainstein 201150 Inclusion: adult (age ≥18 years); type 2 or type N=61 Intervention (n=31): ozone- Allocation concealment: 1 diabetes; Wagner classification stage 2 or 3 Age (years): 63 oxygen; Phase I – tx sessions Unclear Israel or post-debridement stage 4 foot ulcer Gender (% male): 62 4x/wk for 4 wks or granulation in Blinding: Double (patient Funding Source: NR, Race/ethnicity: NR 50% of wound area; max of 1 day and investigator) device supplied by Exclusion: gangrenous foot ulcer; active BMI: NR between txs (5 day week); gas manufacturer osteomyelitis; history of collagen diseases; Pre-albumin: NR concentration: 96% oxygen & 4% Intention to treat analysis hyperthyroidism; pregnancy or nursing; HbA c HbA1c (%): 8.6 (80 lg/ mL) ozone; Phase II – tx (ITT): Yes, all randomized Therapy Type: 1 >10.5%; ABI <0.65; hemoglobin <8 g/dL; liver Smoking: 8% current sessions 2x/wk to complete 12 wk included Ozone-oxygen # Work days missed: NR tx; gas concentration: 98% oxygen Therapy function tests (alanine transaminase, aspartate Withdrawals/dropouts transaminase, or c-glutamyl transpeptidase) ABI: 26% 0.65-0.8; 23% 0.8-1.0; 46% & 2% (40 lg/mL) ozone >1.0 adequately described: elevated to more than three times the upper Comparator (n=30); sham tx; Yes normal limit; serum creatinine >2.5 mg/dL or Wound location: foot device circulated room air only dialysis; known allergy to ozone Wound type: diabetic Wound size (cm2): ozone 4.9, sham 3.5 ALL: debridement; daily wound Wound grade: Wagner 2-4 dressings as needed; tx Wound duration: 15.8 years sessions=26 min Comorbid conditions (%): Antibiotic Use: as needed History of DM: 100% Treatment Duration: 12 weeks Follow-up Duration: none Study Withdrawal (%): 44 (27/61) Treatment Compliance: NR

145 Advanced Wound Care Therapies for Non-Healing Diabetic, Venous, and Arterial Ulcers: A Systematic Review Evidence-based Synthesis Program

Study, Year Intervention Patient Characteristics Country Inclusion/Exclusion Criteria Comparator Study Quality Ulcer Type Funding Source Length of Follow-up Wang 201145 Inclusion: chronic non-healing foot ulcers of N=77 (of 86 randomized) Intervention: HBOT (n=45, 2 with Allocation concealment: more than 3 months duration Age (years): 62 bilateral ulcers); ATA of 2.5; 90 min Inadequate (odd-even) Taiwan Gender (% male): NR 5 days/wk for 4 wks (20 sessions); Blinding: No Funding Source: Exclusion: cardiac arrhythmia or pacemaker; Race/ethnicity: Asian multi-place hyperbaric chamber + Research Fund pregnancy; skeletal immaturity; malignancy BMI: NR standard treatment Intention to treat analysis through a University Pre-albumin: NR (ITT): No Comparator: extracorporeal HbA1c(%): 8.4 Therapy Type: Smoking: NR shockwave therapy (dermaPACE Withdrawals/dropouts Hyperbaric Oxygen # Work days missed: NR device) (n=41, 5 with bilateral adequately described: (HBOT) ulcers); dosage dependent on Yes ABI: 0.99 (HBOT 0.91, control 1.07; p=0.06 between groups) ulcer size – min of 500 impulses 2 flux Wound location (%): plantar foot 71; at E2 (0.23mJ/ mm density) at 4 shocks/sec; 2 times/ dorsal foot 29 wk for 3 wks (6 sessions) Wound type: diabetic 2 Wound size, cm (median): HBOT 7; Antibiotic Use: per physician control 4 (p=0.06) Treatment Duration: 3-4 weeks Wound grade (Wagner) (%): NR depending on therapy; some Wound duration, months (median): subjects received 2nd course

HBOT 6; control 6 Follow-up Duration: none Comorbid conditions (%): Study Withdrawal (%): 10 (n=9) History of DM: 100% Treatment Compliance: NR Wieman 199831 Inclusion: type I or II diabetes; ≥1 full thickness N=382 Intervention: becaplermin gel# Allocation concealment: (IAET stage III or IV) wound of lower extremity Age (years): 58 Unclear United States (23 A) 30ug/g (n=132): amount present for ≥8 weeks; transcutaneous oxygen Gender (% male): 67 sites) determined weekly at study visits Blinding: Unclear tension (TcPo ) ≥30 mmHg Race/ethnicity: white: 81; black: 12; 2 B) 100ug/g (n=123): amount (reported to be double- Funding Source: Asian: 0.3; Hispanic: 6.3; other: 0.3 determined weekly at study visits blind but not specified) Industry Exclusion: osteomyelitis affecting target BMI: NR Pre-albumin: NR Comparator (n=127): placebo Intention to treat analysis Therapy Type: ulcer; post-debridement ulcer size exceeding 2 HbA c (%): NR (ITT): No Platelet-derived 100 cm ; non-diabetic ulcers; cancer; other 1 ALL: daily treatment with gel, concomitant diseases; receiving treatment or Smoking: NR sharp debridement; moist saline Growth Factors # Work days missed: NR Withdrawals/dropouts medication (radiation therapy, corticosteroids, dressings (2x/day), off-loading adequately described: chemotherapy, or immunosuppressive agents); ABI: NR Antibiotic Use: as needed Yes nursing, pregnant, or of childbearing potential Wound location: 55% foot dorsum Treatment Duration: 20 weeks not using contraception Wound type: diabetic Wound size: 2.7 cm2 Follow-up Duration: 3 months Wound grade: IAET stage III/IV Study Withdrawal (%): 19 Wound duration: 49 weeks Treatment Compliance: 97.4% (no Infection: NR details provided) Comorbid conditions (%): NR #Regranex 0.01%

NR=Not Reported; HbA1c=Hemoglobin A1c; DM=Diabetes Mellitus; HTN=Hypertension; CAD/CVD=Coronary Artery Disease/Cardiovascular Disease; PVD=Peripheral Vascular Disease; ITT=Intention to Treat Analysis; BMI=Body Mass Index; PRP=Platelet Rich Plasma; rhPDGF=recombinant human Platelet-derived Growth Factor; IAET=International Association of Enterostomal Therapy; IPC=Intermittent Pneumatic Compression; ABI=Ankle Brachial Index; NPWT=Negative Pressure Wound Therapy; HBOT=Hyperbaric Oxygen Therapy *The Wagner grade system is a classification based on 6 wound grades (scored 0 to 5) to assess ulcer depth 146