Update on evidence and science
New clinical data in DFU wounds Retrospective cohort evaluation Site: Southtees, UK Main Inclusion criteria: DFU, < wound size reduction in 4 weeks Verum Group: Standard care + Sham Group: Standard care alone Patients enrolled: 40 Duration: 6 months Status: Paper published Diabetic Foot & Ankle 2016. 2016 Sharon D. Hunt and Fredrik Elg. 2
There was no significant difference at baseline between the groups Tests of difference between groups at baseline [t-test, Chi-square] 1 1,00 Critical (p<0.05) p-value 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 p<0.05 0,00 Age HbA1c Wound size Healing rate Ulcer type History SINBAD Neuropathy Vascular Off-loading 1 Continuous variables compared using t-test, nominal variables compared using Chi-square test 3
healed wounds 16 20/20 patients Diabetic foot ulcer Significantly higher rates of wound closure/healed wounds Week of treatment n=20+20 14 12 10 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Control Sharon Dawn Hunt, Fredrik Elg. Clinical effectiveness of hemoglobin spray ( ) as adjunctive therapy in the treatment of chronic diabetic foot ulcers. Diabetic Foot & Ankle 2016, 7: 33101 - http://dx.doi.org/10.3402/dfa.v7.33101 4
% wound size change 0 Diabetic foot ulcer Wound size reduction vs. standard care Week of treatment 20/20 patients n=20+20 4 8 12 16 20 24 28-20 -26-40 -39-37 -43-60 -63-53 -58-63 -80-78 -100-89 -91-96 -96-95 -120 Control Sharon Dawn Hunt, Fredrik Elg. Clinical effectiveness of hemoglobin spray ( ) as adjunctive therapy in the treatment of chronic diabetic foot ulcers. Diabetic Foot & Ankle 2016, 7: 33101 - http://dx.doi.org/10.3402/dfa.v7.33101 5
% sloughy tissue coverage 60 Diabetic foot ulcer Rapid reduction of wound slough/sloughy tissue coverage Week of treatment 20/20 patients n=20+20 50 50 50 40 40 30 24 20 10 19 17 14 11 9 0 0 0 0 0 0 1 1 0 4 8 12 16 20 24 28 Control Sharon Dawn Hunt, Fredrik Elg. Clinical effectiveness of hemoglobin spray ( ) as adjunctive therapy in the treatment of chronic diabetic foot ulcers. Diabetic Foot & Ankle 2016, 7: 33101 - http://dx.doi.org/10.3402/dfa.v7.33101 6
4,5 4 3,5 3,60 4,1 Diabetic foot ulcers Pain score Week of treatment 20/20 patients n=20+20 3 2,5 2,45 2 1,5 1,44 1,22 1,17 1 0,5 0 0,72 0,72 0,44 0,25 0,05 0 0 0 0 0 0 4 8 12 16 20 24 28 Week Control Sharon Dawn Hunt, Fredrik Elg. Clinical effectiveness of hemoglobin spray ( ) as adjunctive therapy in the treatment of chronic diabetic foot ulcers. Diabetic Foot & Ankle 2016, 7: 33101 - http://dx.doi.org/10.3402/dfa.v7.33101 7
New clinical data in chronic, slow healing wounds Retrospective cohort evaluation Site: Southtees, UK Main Inclusion criteria: < wound size reduction in 4 weeks, wounds of different etiologies Verum Group: Standard care + Sham Group: Standard care alone Patients enrolled: 100 Duration: 6 months Status, Finished, paper submitted The clinical effectiveness of haemoglobin spray as adjunctive therapy in the treatment of chronic wounds; THE JOURNAL OF WOUND CARE VOL 26, NO 9, SEPTEMBER 2017, Fredrik Elg, Sharon Dawn Hunt 8
% sloughy tissue coverage Pain score healed wounds % wound size change 50 45 40 35 30 25 20 15 10 5 0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627 0-10 -20-30 -40-50 -60-70 -80-90 -100 4 8 12 16 20 24 26-12 -14-41 -52-63 -67-73 -75-87 -92-94 -93-91 -89 Control Control 50 45 40 38 47 5 4,5 4 4,6 35 30 25 32 26 3,5 3 2,5 3,2 2,8 2,9 20 15 10 5 0 11 6 4 4 4 0 0 0 0 0 1 1 0 4 8 12 16 20 24 26 2 1,5 1 0,5 0 1,3 0,7 0,8 0,1 0,2 0,2 0,3 0,2 0,3 0,2 0,3 0,2 0 4 8 12 16 20 24 26 Control Control The clinical effectiveness of haemoglobin spray as adjunctive therapy in the treatment of chronic wounds; THE JOURNAL OF WOUND CARE VOL 26, NO 9, SEPTEMBER 2017, Fredrik Elg, Sharon Dawn Hunt 9
New clinical data in slow healing & sloughy wounds Retrospective cohort evaluation Site: Southtees, UK Main Inclusion criteria: < wound size reduction in 4 weeks, > slough coverage Verum Group: Standard care + Sham Group: Standard care alone Patients enrolled : 200 Duration: 6 months Status, Finished, paper accepted CLINICAL EFFECTIVENESS OF HAEMOGLOBIN SPRAY AS ADJUNCT THERAPY IN SLOUGHY WOUNDS PAPER ACCEPTED Fredrik Elg, Sharon Dawn Hunt 10
% sloughy tissue coverage Average pain score healed wounds % wound size change 100 90 0 4 8 12 16 20 24 26 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 1011121314151617181920212223242526272829-20 -40-60 -80-100 -120-27 -87-32 -93-57 -63-68 -71-74 -96-97 -98-98 -98 Standard Control 70 60 58 7 6 6,2 50 44 5 40 30 20 10 0 29 17 8 6 5 5 5 1 0 0 0 0 1 1 0 4 8 12 16 20 24 26 4 3 2 1 0 3,4 1,9 1 0,6 0,3 0,4 0,1 0,2 0,1 0,2 0,2 0,2 0,2 0,1 0,2 0 4 8 12 16 20 24 26 Standard Standard CLINICAL EFFECTIVENESS OF HAEMOGLOBIN SPRAY AS ADJUNCT THERAPY IN SLOUGHY WOUNDS PAPER ACCEPTED Fredrik Elg, Sharon Dawn Hunt 11
Comparison with other oxygenating devices 12
Substantial body of evidence Keynumbers for publications TOTAL Number of RCTs, published 2 Non-randomized retrospectively controlled 10 Case series > with 1 or more patients 43 Case series > with 10 or more patients 19 13
EpiFix has been demonstrated as the new benchmark Results of EpiFix vs Apligraf trial 9 7 5 45% 85% 95% 4 weeks 6 weeks Inclusion criteria: DFUs with less than reduction in wound size during 2-week run-in period including Camboot offloading Treatment: Off-loading switched to Camwalker and Apligraf or EpiFix groups, grafts applied every week plus non-adherent layer (Adaptic Touch), a moisture-retentive dressing (NuGel) and a compressive dressing. Standard care group dressed with a collagen-alginate dressing secured with gauze 3 1 35% 35% 3 Apligraf Epifix Standard Care Source: Zelen, C. M., Gould, L., Serena, T. E., Carter, M. J., Keller, J. and Li, W. W. (2015), A prospective, randomised, controlled, multicentre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J, 12: 724 732. doi:10.1111/iwj.12395 14
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Overview of systematic review methodology (1) HBOT MTOT HACM Hyperbaric Oxygen Therapy Moist Topical Oxygen therapy Human amniotic/chorion membrane Haemoglobin facilitated diffusion MEDLINE search for systematic reviews vs standard or care for chronic ulcers, plus additional expanded search for more recent controlled evaluations not yet included in a systematic review. MEDLINE search for systematic reviews vs standard or care for chronic ulcers, plus additional expanded search for more recent controlled evaluations not yet included in a systematic review. MEDLINE search for systematic reviews vs standard or care for chronic ulcers, plus additional expanded search for more recent controlled evaluations not yet included in a systematic review. MEDLINE search for systematic reviews vs standard or care for chronic ulcers, plus additional expanded search for more recent controlled evaluations not yet included in a systematic review. ( Systematic review OR Meta-Analysis ) AND ( HBOT OR Hyperbaric AND ( Ulcer* or Wound* ): 40 Abstracts reviewed ( Systematic review or meta-analysis ) AND Topical AND Oxygen AND ( Ulcer* or Wound* ): 8 Abstracts reviewed ( Systematic review or Meta-analysis ) AND ( dhacm OR Amniotic* AND ( Ulcer* or Wound* ): 6 Abstracts reviewed ( Systematic review or Meta-analysis ) AND ( Topical OR Spray OR Adjunct ) AND ( Haemoglobin OR Hemoglobin ) AND ( Ulcer* or Wound* ): 9 Abstracts reviewed 16
Overview of systematic review methodology (2) HBOT MTOT HACM Hyperbaric Oxygen Therapy Moist Topical Oxygen therapy Human amniotic/chorion membrane Haemoglobin facilitated diffusion Exclusions: Not chronic wound healing related (i.e. radiation, infection only etc excluded) 21 systematic reviews identified and evaluated for comparative evidence in human chronic ulcers 6 Additional systematic reviews identified during review Exclusions: Not chronic wound healing related (i.e. radiation, acute wounds only etc excluded) 8 systematic reviews selected and evaluated for comparative evidence in human chronic ulcers 7 Additional systematic reviews identified during review Exclusions: Not chronic wound healing related (i.e. radiation, acute wounds only etc excluded) 3 systematic reviews selected evaluated for comparative evidence in human chronic ulcers 5 Additional systematic reviews identified during review Exclusions: Not chronic wound healing related 0 systematic reviews with relevant data identified from MEDLINE search 13 Additional potential reviews identified during review 17
Overview of systematic review methodology (3) HBOT MTOT HACM Hyperbaric Oxygen Therapy Moist Topical Oxygen therapy Human amniotic/chorion membrane Haemoglobin facilitated diffusion Additional search for new comparative evaluations published in 2017 and 2018 that may have been missed in systematic reviews: ( HBOT OR Hyperbaric ) AND ( Randomi* OR Control* ) AND ( Wound* OR Ulcer* ) 0 Additional evaluations identified via de-novo search 27 unique original comparative studies identified and evaluated 8 meeting quality and comparability criteria (results extracted). Additional search for new comparative evaluations published in 2015+ that may have been missed in systematic reviews: ( Topical OR Transcutaneous ) AND Oxygen AND ( Randomi* or Control* ) 4 Additional potential evaluations identified via de-novo search 26 unique original comparative studies identified and evaluated 8 meeting quality and comparability criteria (results extracted). Additional search for new comparative evaluations published in 2015+ that may have been missed in systematic reviews: ( dhacm OR Amniotic* ) AND ( Ulcer* or Wound* ) AND ( Randomi*ed or Control* ) 5 Additional potential evaluations identified via de-novo search 21 unique original comparative studies identified and evaluated 10 meeting quality and comparability criteria (results extracted). Additional search for evaluations missed in systematic reviews: ( Randomi* or Control* ) AND ( Topical OR Spray OR Adjunct ) AND ( Haemoglobin OR Hemoglobin ) AND ( Ulcer* or Wound* ) 6 addition via de-novo search, and reference checks 25 unique original comparative studies identified and evaluated 7 meeting quality and comparability criteria (results extracted). 18
Overview of systematic review methodology HBOT MTOT HACM Hyperbaric Oxygen Therapy Moist Topical Oxygen therapy Human amniotic/chorion membrane Haemoglobin facilitated diffusion MEDLINE search for systematic reviews vs standard or care for chronic ulcers, plus additional expanded search for more recent controlled evaluations not yet included in a systematic review. MEDLINE search for systematic reviews vs standard or care for chronic ulcers, plus additional expanded search for more recent controlled evaluations not yet included in a systematic review. MEDLINE search for systematic reviews vs standard or care for chronic ulcers, plus additional expanded search for more recent controlled evaluations not yet included in a systematic review. MEDLINE search for systematic reviews vs standard or care for chronic ulcers, plus additional expanded search for more recent controlled evaluations not yet included in a systematic review. ( Systematic review OR Meta-Analysis ) AND ( HBOT OR Hyperbaric AND ( Ulcer* or Wound* ): 40 Abstracts reviewed Exclusions: Not chronic wound healing related (i.e. radiation, infection only etc excluded) ( Systematic review or meta-analysis ) AND Topical AND Oxygen AND ( Ulcer* or Wound* ): 8 Abstracts reviewed Exclusions: Not chronic wound healing related (i.e. radiation, acute wounds only etc excluded) ( Systematic review or Meta-analysis ) AND ( dhacm OR Amniotic* AND ( Ulcer* or Wound* ): 6 Abstracts reviewed Exclusions: Not chronic wound healing related (i.e. radiation, acute wounds only etc excluded) ( Systematic review or Meta-analysis ) AND ( Topical OR Spray OR Adjunct ) AND ( Haemoglobin OR Hemoglobin ) AND ( Ulcer* or Wound* ): 9 Abstracts reviewed Exclusions: Not chronic wound healing related 21 systematic reviews identified and evaluated for comparative evidence in human chronic ulcers 8 systematic reviews selected and evaluated for comparative evidence in human chronic ulcers 3 systematic reviews selected evaluated for comparative evidence in human chronic ulcers 0 systematic reviews with relevant data identified from MEDLINE search 6 Additional systematic reviews identified during review 7 Additional systematic reviews identified during review 5 Additional systematic reviews identified during review 13 Additional potential reviews identified during review Additional search for new comparative evaluations published in 2017 and 2018 that may have been missed in systematic reviews: ( HBOT OR Hyperbaric ) AND ( Randomi* OR Control* ) AND ( Wound* OR Ulcer* ) Additional search for new comparative evaluations published in 2015+ that may have been missed in systematic reviews: ( Topical OR Trans-cutaneous ) AND Oxygen AND ( Randomi* or Control* ) Additional search for new comparative evaluations published in 2015+ that may have been missed in systematic reviews: ( dhacm OR Amniotic* ) AND ( Ulcer* or Wound* ) AND ( Randomi*ed or Control* ) Additional search for evaluations missed in systematic reviews: ( Randomi* or Control* ) AND ( Topical OR Spray OR Adjunct ) AND ( Haemoglobin OR Hemoglobin ) AND ( Ulcer* or Wound* ) 0 Additional evaluations identified via de-novo search 4 Additional potential evaluations identified via de-novo search 5 Additional potential evaluations identified via de-novo search 6 addition via de-novo search, and reference checks 27 unique original comparative studies identified and evaluated 26 unique original comparative studies identified and evaluated 21 unique original comparative studies identified and evaluated 25 unique original comparative studies identified and evaluated 8 meeting quality and comparability criteria (results extracted). 8 meeting quality and comparability criteria (results extracted). 10 meeting quality and comparability criteria (results extracted). 7 meeting quality and comparability criteria (results extracted). 19
healing benefits in DFUs are the highest Comparison of mean published healing rates by week vs standard of care in patients with diabetes and lower leg and foot ulcers, across four advanced wound care technologies - excluding studies in amputation candidates with gangrene and data with treatment refusers as controls HBOT MTOT HACM Hyperbaric Oxygen Therapy including only standard care controlled data* Gaseous Moist Topical Oxygen therapy (including intermittent delivery)* Human amniotic/chorion membrane including frozen and dehydrated* Continuous haemoglobin facilitated oxygen diffusion * Unhealed patients by week* Unhealed patients by week* Unhealed patients by week* Unhealed patients by week* 9 9 9 9 7 7 7 7 5 5 5 5 3 3 3 3 1 1 1 1 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 RR (relative chances of healing by 24 weeks) RR (increased chance of healed at 24 weeks RR (increased chance of healed at 24 weeks RR (increased chance of healed at 24 weeks HBOT 1,68 0 1 2 3 4 HBOT increases chances of healing by 68% * Pooled unweighted data from Duzgun 2008, Fedorko 2016, Kessler 2003, Löndahl 2010, Ma 2013, Margolis 2013. n=181 vs n=181 (plus Margolis) TOT 1,08 0 1 2 3 4 TOT increases chances of healing by 8% * Pooled unweighted data from Blackman 2010, Driver 2013, Driver 2017, Lavery 2017, Niederauer 2017, Ogenix 2014, Yu 2016 Amniotic membranes 1,76 0 1 2 3 4 HACM increases chances of healing by 76% * Pooled unweighted data from DiDomenico 2016, Lavery 2014, Mohajeri 2016, Snyder 2016, Zelen 2013, Zelen 2016 (n=153 vs n=154) ** The Granlox data not specifically identified as DFUs but rather lower leg ulcers, however investigator review noted that these patients were all diabetic, hence included in DFU selection. 0 1 2 3 4 3,70 increases chances of healing by 27 * Data from Arenberger 2011 (lower leg ulcers)**, Hunt 2017b (Unique DFU subset from three independent evaluations) (n=37 vs n=51) 20
Also, when including only regular standard care Comparison of published healing rates vs standard of care in DFUs, across four advanced wound care technologies, excluding studies with a non-standard, standard care arm, i.e. excluding control arms using gauze and/or petroleum jelly as standard care dressing regimen. HBOT MTOT HACM Hyperbaric Oxygen Therapy including only standard care controlled data* Gaseous Moist Topical Oxygen therapy (including intermittent delivery)* Human amniotic/chorion membrane including frozen and dehydrated* Continuous haemoglobin facilitated oxygen diffusion * Unhealed patients by week* Unhealed patients by week* Unhealed patients by week* Unhealed patients by week* 9 9 9 9 7 7 7 7 5 5 5 5 3 3 3 3 1 1 1 1 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 RR (relative chances of healing by 24 weeks) RR (relative chance of healing by 24 weeks) RR (relative chance of healing by 24 weeks) RR (relative chance of healing by 24 weeks) HBOT 1,68 TOT 1,18 Amniot 1,60 2,98 0 1 2 3 4 HBOT increases chances of healing by 68% * Pooled unweighted data from Duzgun 2008, Fedorko 2016, Kessler 2003, Löndahl 2010, Ma 2013, Margolis 2013, 0 1 2 3 4 TOT increases chances of healing by 18% * Pooled unweighted data from Blackman 2010, Driver 2013, Driver 2017, Lavery 2017, Niederauer 2017, Ogenix 2014, Yu 2016 (n=126 vs n=124) 0 1 2 3 4 HACM increases chances of healing by * Pooled unweighted data from DiDomenico 2016, Lavery 2014, Snyder 2016, Zelen 2013, Zelen 2016 (n=126 vs n=124) 0 1 2 3 4 increases chances of healing by 198% * Pooled unweighted data from Hunt 2017b (Unique DFU subset from three independent evaluations)** (n=23 vs n=37) ** The Arenberger 2011 data no longer included as the dressing regimen in the control arm used Vaseline cover as primary dressing and cotton pads as secondary dressing. 21
Healing in VLUs are also among highest observed Comparison of published healing rates vs standard of care in VLUs, across four advanced wound care technologies HBOT MTOT** HACM Hyperbaric Oxygen Therapy including only standard care controlled data* Gaseous Moist Topical Oxygen therapy (including intermittent delivery)* Human amniotic/chorion membrane including frozen and dehydrated* Continuous haemoglobin facilitated oxygen diffusion * Wound size vs baseline by week* Wound size vs baseline by week* Wound size vs baseline by week* Wound size vs baseline by week* 1 1 1 1 1 1 1 1 0 4 8 12 0 4 8 12 0 4 8 12 0 4 8 12 Speed (%/week) 6.86x Speed (%/week) 1.58x Speed (%/week) 1.55x Speed (%/week) 5.33x HBOT increases mean chronic VLU healing speed by >50 TOT increases mean chronic VLU healing speed by 58% HACM increases mean chronic VLU healing speed by 55% increases mean chronic VLU healing speed by >50 * Data from Hammarlund 1994 (note very small sample n=8+8 * Pooled unweighted data from Sultan 2016, Tawfick 2009 (n=113 vs n=102), **However control groups based on patient choice, not randomised * Pooled unweighted data from Bianchi 2018, Serena 2014 (n=105 vs n=88) * Pooled unweighted data from Arenbergerova 2013 and Hunt 2017b (VLU subset from three independent evaluations) (n=50 vs n=45) 22
Studies currently underway UK: RCT on DFU (20/20) Portugal: Italy: Asia: Retrospectively controlled cohort study (DFU) Retrospectively controlled cohort study (VLU) RCT Pilot HBOT+GX / HBOT / SoC Outlook US: Phase III trial on DFU patients 23
More than 60 scientific publications provide substantial evidence: Speed Save money >5 faster healing Safety >60,000 Patients treated in >30 countries >5 cost saving potential Quality of life Substantial and immediate pain reduction 24
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