Advice
Clinical and technical evidence
Clinical and technical evidence
A literature search was carried out for this briefing in accordance with the interim process and methods statement. This briefing includes the most relevant or best available published evidence relating to the clinical effectiveness of the technology. Further information about how the evidence for this briefing was selected is available on request by contacting mibs@nice.org.uk.
Published evidence
Five studies are included in this briefing. These studies were selected because they were the highest-quality evidence and included the largest patient populations. They suggest that EpiFix may offer improved healing over standard wound-care dressings and bio-engineered living cellular constructs such as Apligraf.
Table 2 summarises the clinical studies and their individual strengths and limitations.
Overall assessment of the evidence
Two studies included in the table were written by the same group of authors (Zelen et al.). Four of the studies were funded by the company. A total of 571 people are recorded in the studies, but the total number of people in the studies is not clear because the trials include overlapping populations. Two studies included people with venous leg ulcers and the other 3 included people with diabetic foot ulcers. Most studies used time-to-total healing as an outcome, which is a valid outcome, and there is sufficient follow‑up. The comparisons of EpiFix and bio-engineered living cellular constructs are less helpful in judging effectiveness in NHS practice because these technologies are not in widespread use. All studies took place in centres in the US and so this may also limit the generalisability of findings to UK practice. Four other studies are ongoing and 5 have been completed but not published.
Table 2 Summary of clinical evidence
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Study size, design and location |
Randomised controlled multicentre clinical trial in 109 people with non-healing full-thickness venous leg ulcers in 15 centres in the US. |
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Intervention and comparator(s) |
52 people had EpiFix and multilayer compression and 57 had standard dressings with multilayer compression therapy. |
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Key outcomes |
12‑week outcomes: 31/52 (60%) VLUs treated with EpiFix had completely healed compared with 20/57 (35%) for those treated with standard care (p=0.0128). Mean percentage wound reduction was 66% for EpiFix and 40% for standard care. Mean wound size was adjusted for baseline wound size, adjusted mean wound size for EpiFix was 2.82 cm2 compared with 4.81 cm2 for standard care (p=0.0435). 16‑week outcomes: Mean percentage wound reduction was 72% for EpiFix and 39% for standard care. Adjusted mean wound size was 2.38 cm2 for EpiFix and 4.90 cm2 for standard care p=0.0098. |
|
Strengths and limitations |
Wide inclusion criteria including comorbidities such as diabetes. Randomised controlled trial. This study was sponsored and funded by MiMedx. |
|
Study size, design and location |
Multicentre randomised controlled trial in 84 people with venous leg ulcers in 8 centres in the US. |
|
Intervention and comparator(s) |
53 people had EpiFix and multilayer compression and 31 had standard dressings with multilayer compression therapy. |
|
Key outcomes |
40% wound closure at 4 weeks was used as a surrogate end point for complete healing and was the primary outcome of the study. At 4 weeks, 62% of ulcers in the EpiFix group and 32% of ulcers in the control group had reduced in size by more than 40% (p=0.005). In the EpiFix group the mean reduction in wound size was 48.1% compared with 19% in the control arm. |
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Strengths and limitations |
This study uses a surrogate end point for complete healing at 4 weeks. The suitability of this was tested at 24‑month follow‑up (Serena et al. 2015) using the records of 44 people in the study. In this group, 20 people (45.4%) met the primary outcome of the initial study (wound size reduction ≥40% at 4 weeks) and 24 (55%) had not. Complete healing occurred in 80% (16/20) of people in the first group and in 33.3% (8/24) of the second group (p=0.0023). This study was sponsored and funded by MiMedx. |
|
Study size, design and location |
Prospective randomised controlled trial in 60 people with DFUs, in 3 centres in the US. |
|
Intervention and comparator(s) |
Participants were randomised to have treatment with EpiFix+SC (20), Apligraf+SC (20) or SC only with a collagen-alginate dressing (20). EpiFix and Apligraf were applied once a week. SC was as previously described. |
|
Key outcomes |
Complete healing %:
The estimated median healing time was 13 days for EpiFix, 49 days for Apligraf and 49 days for SC only. During the study period, the mean number of Apligraf used was 6.2 per person (total cost: $9,276 per person), compared with 2.15 per person ($1,669) for EpiFix. |
|
Strengths and limitations |
The authors state that the study population was not large enough to perform any subgroup analyses. The study was sponsored and funded by MiMedx. |
|
Study size, design and location |
Prospective, randomised, controlled trial in 100 people with DFUs in 4 centres in the US. |
|
Intervention and comparator(s) |
32 people had treatment with EpiFix+SC, 33 with Apligraf+SC and 35 with SC only. |
|
Key outcomes |
Complete healing in the 12‑week study period in 97% (31/32) of DFUs treated with EpiFix, 73% (24/33) with Apligraf and 51 (18/35) with SC only. Mean time to heal was 23.6 days for the EpiFix group, 47.9 days for Apligraf and 57.4 days for SC only. Median number of applications used per healed wound was 2.5 (range 1 to 12) for EpiFix and 6 (range 1 to 13) for Apligraf. |
|
Strengths and limitations |
The authors did analyses based on the cost of treatment for EpiFix and Apligraf. These results are of limited use because the costs for SC have not been considered. The study was sponsored and funded by MiMedx. |
|
Study size, design and location |
Retrospective analysis of wound-care-specific data from 218 people with diabetic ulcers from 99 centres in the US. |
|
Intervention and comparator(s) |
63 people were treated with EpiFix and 163 people were treated with BLCC. |
|
Key outcomes |
The data were compared between the 2 groups. The average number of applications was significantly higher for EpiFix (3.5) than for BLCC (2.5). Analyses also showed that median time to wound closure is significantly shorter with BLCC, 93 days compared with 182 days. |
|
Strengths and limitations |
Median time to wound closure was much higher in this study than in those reported by Zelen and colleagues. It should also be noted that this study had a much larger population and appears to have included a wider morphology of diabetic foot ulcers. |
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Abbreviations: BLCC, bio-engineered living cellular constructs; DFU, diabetic foot ulcer; SC, standard care; VLU, venous leg ulcer. |
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Recent and ongoing studies
Ongoing studies
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NCT01693133: Trial of dHACM in the management of diabetic foot ulcers. Status: Recruiting participants. Primary comparator: Standard of care – moist wound therapy and offloading. Expected enrolment: 130. Estimated primary completion date: December 2016. Location: US; Alabama, California, Massachusetts, Ohio, Oregon, South Carolina, Texas, Utah, Virginia.
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NCT02322554: Cellular and tissue-based therapy registry. Status: Recruiting participants. Primary comparator: Other cellular and tissue-based products. Expected enrolment: 50,000. Estimated primary completion date: January 2020. Location: US; Texas.
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NCT02813161: The diabetic foot ulcer registry. Status: Recruiting participants. Primary comparator: Other cellular and tissue-based products, negative pressure wound therapy, debridement, dietary supplement, offloading, hyperbaric oxygen therapy. Expected enrolment: 10,000. Estimated primary completion date: January 2025. Location: US; Texas.
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NCT02813187: Venous leg ulcer registry. Status: This study is enrolling participants by invitation only. Primary comparator: Other cellular and tissue-based products, debridement. Expected enrolment: 10,000. Estimated primary completion date: May 2025. Location: US; Texas.
Completed studies with no results available
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NCT02587104: dHACM in the treatment of diabetic foot ulcers. Primary comparator: None. Enrolment: 16. Completion date: June 2016. Location: Canada; Ontario. Publications: No study results posted.
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NCT02589210: dHACM mesh in the treatment of diabetic foot ulcers. Primary Comparator: None. Enrolment: 10. Completion Date: March 2016. Location: US; Virginia. Publications: No study results posted.
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NCT01657474: Comparative study of two application regimens of amniotic membrane wound graft in the management of diabetic foot ulcers. Primary comparator: Weekly versus biweekly application of EpiFix. Enrolment: 40. Completion date: November 2013. Location: US; Virginia. Publications: No study results posted.
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NCT01552447: Human amniotic membrane grafting and standard of care versus standard of care alone in the treatment of venous leg ulcers. Primary comparator: Standard care – compression therapy/bandage. Enrolment: 98. Completion date: May 2014. Location: US; Virginia, Massachusetts, Oklahoma, Pennsylvania. Publications: No study results posted.
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NCT01552499: Comparative study of amniotic membrane wound graft In the management of diabetic foot ulcers. Primary comparator: Standard care. Enrolment: 25. Completion date: August 2012. Location: US; Virginia. Publications: No study results posted.