Study reference

(first author, publication year)

Appropriate and clearly focused question?

Yes/no

Comprehensive and systematic literature search?

Yes/partial yes/ no

Description of included and excluded studies?

Yes/partial yes/ no

Description of relevant characteristics of included studies?

Yes/partial yes/no

Assessment of scientific quality of included studies?

Yes/partial yes/no

Enough similarities between studies to make combining them reasonable?

Yes/partial yes/ no

Potential risk of publication bias taken into account?

Yes/partial yes/ no

Potential conflicts of interest reported?

Yes/partial yes/ no

Jones, 2013

Yes

Yes

Yes

Yes

Yes

No

No

No

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Jones, 2013

Type of study: Cochrane systematic review including 17 RCT’s

A. Brown-Etris, 2000

B. Burdge, 2000

C. Duhra, 1992

D. Falanga, 1998

E. Goedkoop, 2010

F. Jankunas, 2007

G. Krishnamoorthy, 2003

H. Lindgren, 1998

I. Liu, 2004

J. Navratilova, 2004

K. Omar, 2004

L. Paquet, 2005

M. Poskitt, 1987

N. Salomon, 2002

O. Tausche, 2003

P. Teepe, 1993

Q. Warburg, 1994

Inclusion criteria:

Types of studies:

Trials where the allocation of participants was described as randomised. Cross-over trials only if the outcomes at the point of cross-over were given, as data after this point were not based on comparable baseline groups. No restriction on study reports based on language or publication status.

Patients:

participants of any age, in any care setting, and with venous leg ulceration (which may also be described as stasis or varicose ulceration).

Method of diagnosis:

No standard definition. Also inclusion of participants with arterial, mixed, neuropathic and diabetic ulcers only if the outcomes for those with venous ulcers were reported separately.

Types of interventions:

1. pinch grafts (autografts);

2. split-thickness grafts (autografts);

3. full-thickness grafts (autografts and xenografts);

4. cultured keratinocytes/ epidermal grafts (allografts and

xenografts);

5. artificial skin (allografts).

Outcome measures

Primary outcomes included: objective measures of healing such as relative or absolute rate of change in ulcer area; time to complete healing; or proportion of ulcers healed within the trial

period.

Secondary outcomes included: costs; quality of life; pain; side effects; adverse events; withdrawals and acceptability of treatment.

Date search:

July 2012

N total:

1034 participants

1. Grafts

a. autograft (Jankunas 2007; Warburg 1994).

b. fresh or frozen allograft (Burdge 2000; Duhra 1992; Lindgren 1998; Paquet 2005;

Teepe 1993).

c. bilayered human skin equivalent (Brown-Etris 2000; Falanga 1998).

d. single-layered dermal skin replacement

(Krishnamoorthy 2003; Omar 2004).

e. growth-arrested human keratinocytes and fibroblasts (Goedkoop 2010)

2. Grafts

a. autograft (Tausche 2003)

b. autograft (Poskitt 1987)

c. autograft deliverd on on porcine pads (liu 2004)

d. Autograft (Salomon 2002)

e. frozen allograft (Navratilova, 2004)

1. Standard care

2: Grafts

a. frozen allograft

b. xenograft

c.  autograft

delivered on porcine gelatin microbeads

d.  cultured keratinocyte autograft

e.  yophilised keratinocyte allograft

Length of follow-up:

The studies had a variety of duration of active treatment and follow-up. followup

rates ranged from 81% (Teepe 1993) to 100% (Duhra 1992;

Lindgren 1998)

Loss-to-follow-up:

In four trials, there were dropouts and withdrawals but were assessed to be low risk of bias in this domain as they

accounted for 10% or fewer of the sample size (Krishnamoorthy

2003; Lindgren 1998; Tausche 2003; Warburg 1994).

The trial by Teepe 1993 reported losses to follow-up amounting to around

19% which was adjudged to be high risk of bias.

The trials by Brown-Etris 2000; Burdge 2000 and Salomon 2002 were only

available in abstract form, and subsequent, fuller reports may contain

more information about the fate of withdrawals.

In two studies the number of withdrawals was

not stated (Brown-Etris 2000; Burdge 2000)

1a. Warburg 1994:

no evidence of a significant benefit for autografts over a dressing RR of healing with autografts 0.89, 95% (CI 0.34 to 2.31). Jankunas2007:  large difference in healing rates in favour of autografts RR of healing 42.93, 95% CI 2.72 to 677.16)

1b.  Pooling the three trials using a fixed-effect model (Chi² 0.76; degrees of freedom (df ) = 1; P value 0.38; I² = 0%) showed that there was no significant difference in healing with allografts over standard care (RR 1.62, 95% CI 0.79 to 3.33)

1c.  Pooling these three trials using a fixed-effect model (Chi² 0.02; df = 1; P value 0.88; I² = 0%) showed that there was no significant difference in healing with allografts over standard care (RR 3.73, 95% CI 0.80 to 17.45).  Pooled analysis: pooling all five trials (125 participants) using a fixed effect model (Chi² 1.65; df =3; P value 0.65; I² = 0%) indicated significantly higher healing rates with allografts than dressings (RR 2.00, 95% CI 1.04 to 3.84)

1d.  Pooling the results from these two trials using a fixed-effect model (Chi² = 0.55; df = 1; P value 0.46; I² = 0%) yields a RR of healing with the artificial skin compared with simple dressings of 1.51 (95% CI 1.22 to 1.88)

1e. There was no evidence of benefit associated with 12 pieces of dermal skin replacement (weekly for 11 weeks) compared with standard care (Krishna-moorthy) (RR 2.5, 95% CI 0.59 to 10.64) There was no evidence of overall benefit associated with four pieces of dermal skin replacement (at baseline, one, four and eight weeks) in the two studies (RR 3.04, 95% CI 0.95 to 9.68)

2a. expressed as proportions healed (RR 1.04, 95% CI 0.56 to 1.94) or percentage reduction in area (14.37% greater reduction with autograft, 95% CI -13.76 to 42.5).

2b.  The increase in ulcers healed at 12 weeks with pinch grafting 72%(18/25)

compared with 46%(13/28) xenograft) just missed the traditional cut-off for statistical significance (Chi² 3.55; df = 1; P value 0.06). The risk ratio for healing with autograft was 1.55 (95% CI 0.97 to 2.47). There was, however, a significant benefit

associated with pinch grafts when the data were analysed by time to healing and the number of ulcers healed (authors’ log rank Chi² 4.1; P value < 0.05).

2c.  There was no difference in the number of people healed at the end of the trial (RR 1.0, 95% CI 0.08 to 11.93), with only 20% healing in each group

2d.  There was no statistically significant

difference in the number of people healed at the end of the trial (RR 1.04, 95% CI 0.56 to 1.94: our intention-to-treat analysis assuming the non-healing of dropouts)

2e.  no difference in healing rates at the end of the trial (RR 1.05, 95% CI 0.81 to 1.36)

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Mostow, 2005

Type of study:

RCT

Setting:

Multicenter trial

Country:

USA

Source of funding:

Not stated

Inclusion criteria:

1. Patient age ≥18 years

2. Ulcer size 1-64 cm²

3. Ulcer depth extends through both the epidermis and dermis, with no exposed tendon or bone

4. Ulcer duration >1 month

5. Ulcer location between and including the knee and ankle

6. Viable wound bed with granulation

Tissue

Exclusion criteria:

Other etiology, additional vascular, immunologic, hematologic or inflammatory diseases, diabetes, ABPI <0.8

N total at baseline:

120

Intervention: 62

Control: 58

Important prognostic factors¹:

age ± SD:

I: 63 ± 2

C: 65 ± 2

Sex:

I: 47% M

C: 36% M

Groups are comparable at baseline

porcine extracellular matrix graft plus compression

Compression alone

Length of follow-up:

6 months

Loss-to-follow-up:

Twenty-four patients (20%) of the 120 —12 in the SIS wound matrix arm and 12 in the standard-care arm—did not complete the planned 12-week follow-up for reasons

other than ulcer healing.

Results at the end of the 12-

week treatment period showed that healing occurred in 55% (34/62) of patients who received SIS wound matrix plus standard care vs 34% (20/58) of patients who received

standard care alone (P = .0196)

RR 1.59 95% CI 1.06-2.42 (reported for healing with matrix)

An odds ratio calculation indicated that patients

receiving SIS were 2.3 times more likely to have complete wound healing as compared with patients receiving

standard care alone (odds ratio, 2.307)

The Cox proportional hazards regression analysis showed an estimated probability of successful healing of 63% at 12 weeks for the SIS wound matrix

group and 40% for the standard-care group. A significant difference between the survival curves for the two groups (P = .0226) was indicated

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Wille, 2011

Type of study:

RCT

Setting:

Single center trial

Country:

USA

Source of funding:

Grant from Hy-Gene Biomedical

Corp, Columbus, Ohio

Inclusion criteria:

1. Clinically confirmed venous insufficiency (venous duplex evaluation with reflux) without diminution of arterial flow.

2. All of the ulcers were of the lower extremities and measured at least 2.5 cm in one axis with a depth of up to 4–6mm but without exposed fascia, bone, or tendon.

3. All wounds were unresponsive to previous treatments including various occlusive dressings, compression therapy, topical growth factors, hyperbaric oxygen, split-thickness skin grafts, or systemic therapy.

Exclusion criteria:

BMI > 38, ongoing systemic or local infections, history of recent treatment with immune suppressants or steroids.

Outcome measures:

1. wounds healed, i.e., patients’ wounds closed as visually confirmed, reflecting dimensional measurements of 0.0 cm, the absence of eschar, scab, and discharge29; 2. fraction of wound area closure, i.e., area closure was determined by direct patient wound tracings; 

3.  fraction of wound volume closure determined by sampling peripheral and central points within the wound using a calibrated probe to yield an estimated average wound depth.

Study duration:

12 weeks

N total at baseline:

15

Intervention: 10

Control: 5

Important prognostic factors¹:

age ± SD:

I: 62 ± 6

C: 64 ± 9

Duration of wounds:

I: 25 ± 8 months

C: 32 ± 16 months

Groups are not comparable at baseline:

Initial average wound size was significantly greater by a factor of two in the autograft (28.9 ± 9.8 cm2) vs. the SCG (13.83 ± 3.6 cm2).

The autograft wound volumes were also significantly greater (12.6 ± 5.8 cm3) than the SCG wounds (4.3 ± 1.6 cm3).

Cultured epidermal

Autograft (CEA)

Standard care (according to the standard of care protocols of the Wound Care Centers in the US, i.e. controlled debridement and layered compression.

Length of follow-up:

1 year

Loss-to-follow-up:

All patients completed the study and follow-up period.

Complete wound closure occurred in 80% (8/10) of the AG patients, with an average of 1.5 grafts/patient to achieve wound closure. In contrast, only 20% (1/5) of the SCG patients achieved closure. There was no statistically significant correlation between the time of wound closure and the initial size (area) of AG wounds by linear regression analysis (r50.55).

There was a mean reduction of 77% wound area for the AG over the study course

(T0wk=28.9 cm2/T12wk =6.6 cm2) versus a reduction of 62% for the SCG wounds.

(T0wk=13.8 cm2/T12wk =5.3 cm2).

The average time of wound closure was 4.1±1.8 (N=8) weeks for all successfully

closed CEA-treated AG wounds, while the single

closed wound in the SCG group occurred at Week 12.

the rate of healing for the AG was shown to be significantly better than the SCG (AG= 0.80 cm2/day vs. SCG= 0.11 cm2/day; ANCOVA/T3SOS, p < 0.001; Mann–Whitney nonparametric, p < 0.019).

Kaplan meier plot shows 50% complete closure for AG at week 5 and all events had occulted in week 7. For the SCG group only one event occured in week 12.

In a 1-year evaluation of study subjects’ wounds 2 more patients healed at followup.

Ninety percent (9/10) of the AG-treated wounds had

closed or remained closed compared with 20% (1/5) of theSCG-treated wounds.

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Harding, 2013

Type of study:

RCT

Setting:

Open label, prospective multicentre study

Country:

USA, UK, Canada

Source of funding:

Smith & Nephew Wound Management, Hull, UK, and Shire Regenerative Medicine, San Diego, California, USA.

Inclusion criteria:

1. Patients ≥ 18 years

2. VLU located between the knee and ankle (at the level of, and including, the lateral and medial malleolus) that was present for at least 2 months and no more than 5 years prior to screening.

3. The patient’s ulcer had to

(i) be 3–25 cm2 in size; (ii) have a typical appearance of a VLU without exposure of muscle, tendon or bone and (iii) have clean, granulating base with minimal adherent slough, suitable to receive a skin graft.

4. Ulcers reduction in size

(cm2) by less than 50% while under compression therapy during the 2-week screening period

5. ABPI between 0.8 and

1.2 and venous disease had to be confirmed by duplex ultrasonography to demonstrate reflux of >0.5 seconds in saphenous, calf perforator or popliteal veins.

Exclusion criteria:

1. Sinus tracts within the ulcer or evidence of a wound infection (purulence and/or odour), cellulitis and/or confirmed osteomyelitis.

2. Morbid obesity, skin diseases near study ulcer, malignant disease within 5 years, severe peripheral vascular disease or renal disease, congestive heart failure, cell anaemia, thalassemia or uncontrolled diabetes.

3. Patients who had received immune suppressants, systemic corticosteroids, cytotoxic chemotherapy or topical steroids for more than 2 weeks and within 1 month of initial screening or who had a history of radiation at the ulcer site.

4. Patients with a known allergy to bovine products or components of the compression bandage, or who could not tolerate compression bandage therapy, had received an investigational drug within 30 days of randomisation or had been previously treated with HFDS

and/or other tissue-engineered materials.

Study duration:

12 weeks

N total at baseline:

Intervention: 186

Control: 180

Important prognostic factors¹:

age ± SD:

I:  67.9 (13.8)

C:69.1 (12.4)

Sex:

I: 46.2 % M

C: 46.1 % M

Median ulcer size, cm2

(range)

I: 7.4 (2.4–28.2)

C: 7.2 (2.3–26.6)

Groups are comparable at baseline

human fibroblast derived

dermal substitute (HFDS) plus four-layer compression

therapy

Compression therapy alone

Length of follow-up:

Loss-to-follow-up:

total of 10% (19 of 186) of patients in the HFDS group discontinued the study early compared with 23% (41 of 180) of patients in the control group. The reasons for early

discontinuation were AE (3% in the HFDS group versus 6%

in the control group), patient’s own request (2% versus 9%), patient lost to follow-up (2% versus 3%) and ‘other’ (4% from each group).

34% (64/186) of the patients in the HFDS group experienced healing by week 12 compared with 31% (56/180) patients in the control group (P =0.235,

OR=1.40, 95% CI=0.80, 2.41)

For the subgroup of patients with ulcer duration of 12 months or less, healing

by week 12 was observed in significantly more patients in

the HFDS group compared with the control group, 49 (52%) of 94 patients versus 36 (37%) of 97 patients, respectively (P =0.029, OR 2.37, 95% CI=1.08, 5.14)

In the subgroup of patients with ulcers 10 cm2 or less,

complete healing at week 12 was observed in 55 (47%) of

117 patients in the HFDS group compared with 47 (39%) of 120 patients in the control group, no statistical significance

For the full ITT population, 96 (52%) of 186 patients in the HFDS group and 88 (49%) of 180 patients in the control group achieved complete healing by week 24. No significant difference between treatment groups was observed in the time to healing (P =0·660, hazard ratio=1.07, 95% CI=0.80, 1.43).

At week 12, the median

percentage reduction in ulcer area was 83.7% in the HFDS

group compared with 73.0% in the control group.

The overall incidence and type of AEs were comparable

between the HFDS and control groups. 146 (78%) of 187 patients in the HFDS group reported 444 AEs and 138 (77%) of 179 patients in the control group reported 472 AEs (P =0.900).

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Serena, 2014

Type of study:

RCT

Setting:

Multicenter, open label study

Country:

USA and UK

Source of funding:

MiMedx Group, Inc., Marietta, GA.

Inclusion criteria:

1. Age 18 or older

2. ABI >0.75

3. Presence of a VLU extending through the full thickness

of the skin but not down to muscle, tendon, or bone

4. VLU present for at least 1 month

5. VLU is a minimum of 2 cm2 and a maximum of 20 cm2

6. VLU has been treated with compression therapy for at

least 14 days

7. Ulcer has a clean, granulating base with minimal adherent slough

Exclusion criteria (most relevant):

1. Ulcer caused by a medical condition other than venous

insufficiency

2. Exhibits clinical signs and symptoms of infection, uncontrolled diabetes (HbA1c >10%), suspicious for cancer

3. History of more than 2 weeks treatment immunosuppressant, cytotoxic chemotherapy, or

application of topical steroids within 1 month

4. History of radiation at ulcer site

Study duration:

4 weeks

N total at baseline:

84

Intervention: 53

• one dHACM: 26
• two dHACM: 27

Control: 31

Important prognostic factors¹:

age ± SD:

I:  59.0 (17.75)

C:  62.6 (13.53)

Sex:

I: 58.5 % M

C: 48.4 % M

VLU size (cm2)

I: 6.0 (4.33), 18.9% >10 cm2

C: 6.3 (5.27, 19.4% >10 cm2

Groups are comparable at baseline

Dehydrated human amnion/ chorion membrane (dHACM) allograft (EpiFix, MiMedx Group, Inc., Marietta, GA) +  multilayer compression

therapy (MLCT)

multilayer compression

therapy (MLCT)

Length of follow-up:

No follow up

Loss-to-follow-up:

Intervention:

N=2

Reasons:  one withdrew after two visits due to a wound abscess and one was lost to follow-up after three visits

Control:

N=3

Reasons: two

patients withdrew after one visit and one patient withdrew

following randomization as they were unhappy with their group assignment.

Reduction in wound size of ≥40% occurred in significantly greater numbers of patients receiving dHACM vs. those receiving MLCT only (33/53 [62%] vs 10/31 [32%]; p = 0.005).

Patients receiving dHACM in addition to MLCT had a mean reduction in VLU size over the 4-week study period of 48.1% compared with 19.0% in the MLCT only group.

wound area was reduced by a mean of 2.28 ± 3.04 cm2 during the study period in the dHACM group vs. a mean difference of only 0.41 ± 2.68 cm2 in the MLCT group.

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Bianchi, 2018

(Bianchi, 2019)

Type of study:

RCT

Setting:

Multicenter, open label study

Country:

USA

Source of funding:

MiMedx Group, Inc., Marietta, GA, USA.

Inclusion criteria:

Patients over the age of 18 with a full-thickness VLU of at least 30 days duration, with an ABPI of >0.75.

Exclusion criteria:

a VLU penetrating into muscle, tendon or bone; signs of ulcer infection or cancer; a VLU located on the dorsum of the foot; or more than 50% of the ulcer below the malleolus; negative pressure wound therapy or hyperbaric

oxygen therapy in the last 7 days or treatment with other advanced wound care products within the past 30 days.

N total at baseline:

128

Intervention: 64

Control: 64

Study duration:

12 weeks

Important prognostic factors¹:

age ± SD:

I: 61.5 ± 14.9

C: 60.0 ± 10.6

Sex:

I: 63% M

C: 68% M

Baseline wound size, cm2

I: 7.6 ± 6.1

C: 8.3 ± 6.7

Groups are comparable at baseline

Dehydrated human amnion/ chorion membrane allograft (EpiFix, MiMedx Group, Inc., Marietta, GA) +  multilayer compression

therapy (MLCT)

multilayer compression

therapy (MLCT)

Length of follow-up:

4 weeks

Of the subjects, 19 were excluded from analysis, 12 from the EpiFix group and 7 from the control group. Nine subjects were excluded from final analysis due to absolute protocol deviations.

7 subjects had to be withdrawn early due to non-study-related serious adverse events precluding their ability to participate in the study or the collection of ongoing data.

3 subjects withdrew their consent and discontinued their participation.

31 of 52 (60%) VLU patients receiving EpiFix completely healed compared with a

healing rate of 20 of 57 (35%) in those treated with standard

care alone (P=.0128).

At the 16 -week follow-up visit, complete VLU healing was observed in 37 of 52 (71%) and 25 of 57 (44%) of those treated with EpiFix or standard care, respectively (P=.00625).

Mean percentage reduction in wound area within 12 weeks was 66% for EpiFix-treated wounds and 40% for wounds not treated with EpiFix

At week 16, mean VLU area was reduced by 72% for EpiFix-treated wounds compared to 39% with standard care.

Adjusting for baseline

wound size, the week 12 adjusted mean for Epi-

Fix (2⋅82 cm2) is significantly lower than the week 12 adjusted mean for standard care (4⋅81 cm2), with a P-value of 0⋅0435.

The week 16 adjusted mean for EpiFix (2⋅28 cm2) is significantly lower than the week 16 adjusted mean for standard care (4⋅90 cm2), with a P-value of 0⋅0098.

A Kaplan–Meier plot of time to heal within 12 weeks by study

group demonstrated a superior wound-healing trajectory for

EpiFix compared to VLUs treated with standard care alone.The log-rank test of equality of the healing function over the two study groups produced a chi-square test statistic of 6⋅4597, P=0⋅011

Rates of healing

for the ITT and PP populations were, respectively, 50% and 60% for those receiving

EpiFix and 31% and 35% for those in the standard care cohort. Within both ITT and PP analyses, these differences were statistically significant; P = 0.0473, ITT and P = 0.0128, PP.

The Kaplan-Meier plot of time to heal within 12 weeks

for the ITT and PP populations demonstrated a superior wound-healing trajectory

for EpiFix compared with VLUs treated with standard care alone.

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Towler, 2018

Type of study:

RCT

Setting:

Head-to-Head comparing trial

Country:

USA

Source of funding:

none

Inclusion criteria:

1. Age ≥18 years

2. Duration of the target VLU >30 days, wound area >1cm2 and <40cm2, wound depth ,<5mm

3.ABPI ranging from >0.5 or biphasic or triphasic Dopler signals in the doralis pedis and posterior tibial arteries.

Exclusion criteria:

1. HbA1c <12% within 90 days of screening visit, serum creatinine concentrations ≥3.0mg/dL within 30 days prior to screening

2. Subject has participated in another clinical trial involving

a device or a systemically administered investigational

study drug or treatment within 30 days of randomization visit

3. history of endstage renal disease, immunosuppression, malnutrition, liver disease, anemia, scleroderma, AIDS/HIV, connective tissue disorder, sickle cell anemia, osteomyelitis, irradiation of affected extremity, chemotherapy within the last 12 months.

4. Sensitivity to potential bovine collagen or agarose (Apligraf), or any of the antibiotics or preservation agents (Theraskin)

5. Subject has leg ulcers secondary to a disease other than

venous ulcers (eg, vasculitis, neoplasm, or hematological

disorders)

6. Subject has been treated with growth factors, engineered tissues, or skin substitutes within 30 d of

randomization

N total at baseline:

31 à 27 completed the study

Theraskin: 15

Apligraf: 12

Study duration:

12 weeks

Important prognostic factors¹:

age ± SD:

Theraskin: 66.3 ± 18.0

Apligraf: 63.7 ± 13.4

Sex:

Theraskin:: 66.7% M

Apligraf: 58.3% M

Baseline wound size, cm2

Theraskin:: 4.94 ± 4.43

Apligraf: 6.37 ± 6.95

Groups are comparable at baseline

Apligraf

(a living, human, bioengineered skin substitute)

+

weekly dressing changes with a nonadherent contact layer of either Mepilex transfer foam or Adaptic and a multilayer compression dressing composed of either Kendall Kerlix (Medtronic, Minneapolis, MN, USA) and Coban (3M, St Paul, MN, USA), or Coban 2 Layer Compression system (3M, St Paul, MN, USA).

Subjects who were highly exudative with strike-through were changed biweekly

throughout the study. Standard multilayer compression dressings were used as

adjunctive therapy over the primary dressing with all subjects throughout the study.

Any wounds that failed to heal after the initial 12 weeks were treated for an additional

8 weeks with multilayer compression therapy alone and followed for delayed healing.

Theraskin

(a cryopreserved human split-thickness skin allograft harvested within 24 hours postmortem from an organ donor who clears standard safety screenings for organ procurement)

+

weekly dressing changes with a nonadherent contact layer of either Mepilex transfer foam or Adaptic and a multilayer compression dressing composed of either Kendall Kerlix (Medtronic, Minneapolis, MN, USA) and Coban (3M, St Paul, MN, USA), or Coban 2 Layer Compression system (3M, St Paul, MN, USA).

Subjects who were highly exudative with strike-through were changed biweekly

throughout the study. Standard multilayer compression dressings were used as

adjunctive therapy over the primary dressing with all subjects throughout the study.

Any wounds that failed to heal after the initial 12 weeks were treated for an additional

8 weeks with multilayer compression therapy alone and followed for delayed healing.

Length of follow-up:

20 weeks

Loss-to-follow-up:

4 subjects did not complete the study, 3 subjects did not receive any graft (failed inclusion criteria n=2, moved n=1). 1 subject received Apligraf but was not compliant and LTFU

Adverse events:

none

At 12 weeks, 93.3% (14/15) of the TheraSkin subjects experienced complete ulcer

healing, whereas 75.0% (9/12) of the Apligraf subjects experienced complete healing.

There was no significant difference (OR 0.227, P5.294).

At 20 weeks, 93.3% (14/15) of the TheraSkin subjects experienced complete ulcer

healing, whereas 83.3% (10/12) of the Apligraf subjects experienced complete healing.

There was no significant difference (OR 0.371, P5.569).

On average 2.27 grafts per subject (n 15) were used in the TheraSkin cohort, whereas 3.33 grafts per subject (n 12) were used in the Apligraf cohort. There was no significant difference in the  mean number of grafts needed between the 2 groups was found (P 5 .119).

The average graft cost per subject in the TheraSkin

cohort ($2495.33/subject) was significantly lower (P 5 .0399) than the average graft

cost per subject in the Apligraf cohort ($4316.67/subject).

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Cazzell, 2019

Type of study:

RCT

Setting:

Multicenter open label trial

Country:

USA

Source of funding:

LifeNet Health, Inc (virginia Beach, VA), the non-profit organization that processes DermACELL

Inclusion criteria:

1. Age ≥21 and ≤80 years, presence of a single target VLU with a CEAP grade 6

2. Duration of the target VLU ≥60 days, absence of infection, wound area ≥1cm2 and <25cm2, wound depth ≤9mm

3. Ability to comply with offloading and dressing change requirements

4. Adequate circulation defined as having at least 1 of the following criteria within the past 60 days: TcPO2 at dorsum of foot ≥30mmHg; ABI ranging from 0.8-1.2, or at least biphasic Doppler arterial waveforms at the dorsalis pedis and posterior tibial arteries

Exclusion criteria:

1. HbA1c <12% within 90 days of screening visit, serum creatinine concentrations ≥3.0mg/dL within 30 days prior to screening

2. Application of biomedical or topical growth factors or livin skin equivalents to the target wound within 30 days prior to screening

3. Recent revascularization procedure to increase bloodflow in the target limb

4. Sensitivity to potential D-ADM processing reagents gentamicin, polymyxin B, vancomycin, N-lauroyl sarcosinate, Benzonase or glycerol

5. Presence of severe peripheral vascular disease, active infection, untreated malignancy, active Charcot’s disease, necrosis, purulence, or sinus tracts in the ulcer that could not be removed by debridement

N total at baseline:

28

Intervention: 18

Control: 10

Important prognostic factors¹:

age ± SD:

I: 64.6 ± 12.9

C: 61.8 ± 16.9

Groups are comparable at baseline

Decellularized acellular dermal matrices (D-ADMs)

Conventional wound care

Length of follow-up:

24 weeks

Loss-to-follow-up:

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Healing rates at 24 weeks for all applications D-ADM and conventional were comparable (29.4% vs. 33.3% resp)

Mean % reduction in wound area from baseline at week 12 49.7% D-ADM vs 28.5% conventional care

Mean % reduction in wound area from baseline at week 24 59.6% D-ADM vs 8.1% conventional care.

Percentage of heals wounds that remained closed at post termination visits D-ADM vs control 100% vs 66.7% at week 4 (p=.2482); 75.0% vs 33.3% at week 8 (p=.3047) and 75.o% vs 33.3% at week 12 *p=.3047)

Artikel

Reden van exclusie

Huidtransplantatie en debridement

Budamakuntla 2017

Onvoldoende patiënten aantal (n=15) en niet vergelijkend

Campbell 2014

Madentherapie

Cedef 2018

Case report, Franstalig

Contreras-Ruiz 2016

Madentherapie

Davies 2015

Madentherapie

De Angelis 2019

Combinatietherapie met dermal substitute

Doerler 2012

Systematische review, relevante studies reeds meegenomen

Everts 2017

17,9% veneuze etiologie

Ferrer-Sola 2017

9,4% veneuze etiologie

Fourgeaud 2016

36% veneuze etiologie, incorrect studiedesign en franstalig artikel

Greaves 2013

Onvoldoende patiënten aantal (n=20) en irrelevante vergelijking

Gualdi 2016

Onvoldoende patiënten aantal (n=5)

Hall 2019

Geen full tekst beschikbaar

Herberger 2011

Aandeel veneuze etiologie niet helder

Hoppe 2012

SR debridement, Gethin 2015 gekozen als leidende SR

Humrich 2018

Onvoldoende aandeel veneuze etiologie

Jimenez-Hernandez 2014

Onvoldoende patiënten aantal

Jprn 2011

Madentherapie

Kadia 2017

Onvoldoende patiënten aantal (n=13)

Klebuc 2017

Narrative review

Landsman 2016

Irrelevante uitkomstmaat

Lauchli 2014

Irrelevante vergelijking (verschillende dressings bij graft)

Ma 2014

Irrelevante uitkomstmaat

Madhok 2013

Oudere SR

Martinez 2016

Voldoet niet geheel aan inclusie criteria

Maslowski 2020

Pilot studie met onvoldoende patiënten

Morton 2013

Guideline, niet gespecificeerd voor chirurgische wondbehandeling

Mudge 2014

Madentherapie

NCT0174305, 2012

Geen studieresultaten beschikbaar

NCT02148302, 2014

Unpublished data

NCT03881267, 2019

Ongoing trial (recruitment phase)

Pla Sanchez 2019

Geen vergelijkend studiedesign en onvoldoende patiënten aantal (n=12)

Salome, Blanes 2014

Uitkomstmaat genezingstendens ontbreekt

Salome, Magela 2014

Uitkomstmaat genezingstendens ontbreekt

Salome 2013

Uitkomstmaat genezingstendens ontbreekt

Shi 2014

Madentherapie

Stott 2016

Samenvatting artikel Gethin

Williams 2019

Case report

Nelson 2016

Voldoet niet aan PICO

Andrejuk, 2016

Voldoet niet aan PICO

Blumberg, 2012

Voldoet niet aan PICO

Conde-Montero, 2020

Voldoet niet aan PICO

Obermayer, 2016

Voldoet niet aan PICO

Serra, 2012

Voldoet niet aan PICO

Serra, 2016

Voldoet niet aan PICO

Tzaneva, 2014

Voldoet niet aan PICO

Wilcox, 2013

Voldoet niet aan PICO

Rainys 2019

Voldoet niet aan patiëntenpopulatie

Shen 2019

Voldoet niet aan patiëntenpopulatie

Topical agents & dressings

Betts, 2018

Conference abstract

Ctri (Gojiva), 2018

Ongoing trial

Ctri (Vamlapana), 2019

Trial in fase van includeren patiënten

DIssemond (b), 2020

Narratieve review

Dissemond (c), 2020

Arteriële en veneuze etiologie samengenomen

Elgarhy, 2020

Groot aandeel DM

Givol, 2019

Irrelevante behandeling + dierstudies

Hongrang, 2019

Geen full tekst beschikbaar

Jull, 2018

Studie protocol

Kkq2h (silver hydrofibrate), 2019

Ongoing trial (not yet recruiting)

Miles, 2019

Studie protocol

Moreno-eutimo, 2018

Diagnose VLU onduidelijk

Morilla-Herrera, 2020

Studie protocol

NCT03662997 (3 multi-layered foam dressings)

Ongoing trial (no results posted)

NCT03589586 (dermacell)

Ongoing trial (recruiting)

NCT03596112 (wound dressing compare)

Ongoing trial (no results posted)

NCT03621592 (wound dressing compare)

Ongoing trial (recruiting)

NCT03903692 (MPS and CMC dressings)

Ongoing trial (recruiting)

NCT04078555 (ENERGI-F703 GEL)

Ongoing trial (not yet recruiting)

NCT04198441 (omeza protocol)

Ongoing trial (recruiting)

NCT03881267 (skin-TE)

Ongoing trial (recruiting)

NCT04178525 (chitosan gel)

Ongoing trial (recruiting)

Pactrial, 2019

Ongoing trial (no results posted)

Probst, 2019

Irrelevante behandeling (timolol)

Purcell, 2018

Aandeel veneuze etiologie onduidelijk

Raju, 2019

Veneuze etiologie 1/3, maar niet uitgesplitst in resultaten

Sigal, 2019

Geen vergelijkende studie

Westby, 2018

Irrelevante uitkomstmaat

Yeowell, 2018

Conference abstract

Zelenikova, 2019

Onvoldoende VLU + groot deel icm DM

Zhang, 2019

Irrelevante therapie en aandeel veneuze etiologie onduidelijk

Atias, 2020

Voldoet niet aan PICO

Bianchi, 2018 (skin grafts)

Voldoet niet aan PICO

Cazzell, 2019 (skin grafts)

Voldoet niet aan PICO

Colenci, 2019

Voldoet niet aan PICO

Dissemond (a), 2020

Voldoet niet aan PICO

Overige behandelingen       

Arvensen 2017

Case series met 11 patiënten

Barrientos, 2014

Niet gespecificeerd voor veneuze etiologie

Bradbury, 2015

Case series

Brinkert, 2013

Combinatietherapie NPWT en saline oplossing

Cetinkava, 2020

Combinatiebehandeling HA+SA+NPWT

Couture, 2016

Geen vergelijkende studie

Cuomo, 2017

Experimenteel VAC device

De Angelis, 2019

Veneuze etiologie niet gespecificeerd

Driver, 2016

Kosteneffectiviteitsstudie

Egemen, 2012

Geen vergelijkende studie, n=20

Elheneidy, 2016

Geen relevante behandeling

Etugoy, 2018

Editorial

Gonzalez, 2017

Handcrafted VAC device (niet gestandaardiseerd)

Greer, 2013

SR niet gespecificeerd voor veneuze etiologie

Hanumanthappa, 2012

Aandeel veneuze etiologie slechts 10%

Hesseler, 2019

SR niet gespecificeerd voor veneuze etiologie (studies voor UCV zijn in richtlijn geïncludeerd)

Huang, 2011

Geen full tekst beschikbaar

Kirsner, 2020

Kosteneffectiviteitsstudie

Kiwanuka, 2012

Narratieve review

Lima, 2017

Onvoldoende aandeel veneuze etiologie

Marston, 2015

Mechanische vs. Elektrische NPWT

Milek, 2019

DM

Morimoto, 2012

Narratieve review

Morimoto, 2013

Case series met 13 patiënten

O’Connell, 2012

Narratieve review

Otero, 2018

Conference abstract

Rivers, 2014

Narratieve review

San Sebastian, 2014

Studieprotocol

Santoro, 2018

Conference abstract

Schintler, 2012

Oude SR+MA NPWT

Semenic, 2018

Onvoldoende patiëntenaantal en diagnostische criteria UCV niet helder

Stone, 2020

DM

Stryia, 2015

Geen full tekst beschikbaar

Tan, 2018

Gecombineerde behandeling VAC+GF, niet gespecificeerd voor ulcera met veneuze etiologie

Tawfick, 2019

Conference abstract

Wu, 2018

N=4, geen vergelijkende studie

Yuvarsi, 2020

Geen full tekst beschikbaar

Zollino, 2017

Geen relevante behandeling

Nelson, 2016

Voldoet niet aan PICO

Dabiri, 2013

Voldoet niet aan PICO

Westby, 2016 (CR protease modulerende matrix VLU)

Voldoet niet aan PICO

Xia, 2019

Voldoet niet aan PICO

Alvarez, 2020

Voldoet niet aan PICO

Armstrong, 2012

Voldoet niet aan PICO

Bianchi, 2018

Voldoet niet aan PICO

Bianchi, 2019

Voldoet niet aan PICO

Burgos-Alonso, 2018

Voldoet niet aan PICO

Elbarbary, 2020

Voldoet niet aan PICO

Harding, 2013

Voldoet niet aan PICO

Kirsner, 2019

Voldoet niet aan PICO

Lantis, 2013

Voldoet niet aan PICO

Moneib, 2018

Voldoet niet aan PICO

Serena, 2014

Voldoet niet aan PICO

Escamilla 2017

Voldoet niet aan uitkomstmaat

Burgos-Alonso, 2017

Voldoet niet aan PICO