granulox health technology assessment - redermis · 2 content-chronic wound care –summary...

1PW0872016 Sept 2016 v1.7; Includes private data pending publication. Pages marked “pending” only. After publication, to be replaced with final data and analysis as validated and published.

Granulox® Health Technology Assessment - The case for haemoglobin spray in South Africa

– A summary of the mode of action, clinical, cost-effectiveness, and health-economic evidence for haemoglobin spray in chronic wound care

http://redermis.com/index.php


2

Content

- Chronic wound care – Summary introduction to a major health burden with large unmet medical needs

- Mode of action – Addressing the chronic hypoxia common to all chronic wounds

- Clinical evidence – Prospective randomised and retrospectively controlled data

- Cost effectiveness – Estimates of cost effectiveness for reimbursement in South Africa

- Sensitivity analysis – Assessment of robustness of cost-effectiveness across patient sub-populations

3

The cost of care for patients with chronic wounds is high

Sources: 1 Posnett J Franks P (2008) The burden of chronic wounds in the UK. Nursing Times 104(3) 44-5. £2.7bn estimate taken as midpoint between £2.3bn and £3.1bn I 2 BBC News, Cost of cancer in UK ‘over 15bn’ a year, 2012, available at: http://www.bbc.co.uk/news/health-20222759 [last accessed: 5 August 2015] I 3 Cancer Research UK, Lung cancer UK price tag eclipses the cost of any other cancer, 2012, Available at: http://www.cancerresearchuk.org/about-us/cancer-news/press-release/2012-11-07-lung-cancer-uk-price-tag-eclipses-the-cost-of-any-other-cancer [last accessed: 5 August 2015]. Note that the estimate for the cost of cancer above also include the total economic cost, not just the cost to the NHS. Copyright infirst HEALTHCARE, reproduced with permission.

0 0.5 1 1.5 2 2.5 3

Prostate cancer £800m

Breast cancer £1.5bn

Lung cancer £2.4bn

Chronic wounds £2.7bn

1

2,3

2

2

Chronic wounds are estimated tocost 3% of the total UK NHS budget and has been estimated to cost £3.1bn1 annually.

Cost of care burden for major disease areas, UK data

http://www.bbc.co.uk/news/health-20222759

http://www.cancerresearchuk.org/about-us/cancer-news/press-release/2012-11-07-lung-cancer-uk-price-tag-eclipses-the-cost-of-any-other-cancer

4

The quality of life impact is also substantial

Source: Adapted from Marion Kerr (2012) Foot Care for People with Diabetes: The Economic Case for Change, Insight Health Economics www.diabetes.org.uk/Documents/nhs-diabetes/footcare/footcare-for-people-with-diabetes.pdf ; Adapted from original report under the terms of the UK Open Government Licence. Copyright infirst HEALTHCARE, reproduced with permission.

A patient with a chronic ulcer has substantially reduced quality of life (-40%) and when the ulceration leads to a major amputation reduced by more than half (-58%)-58%

-40%

http://www.diabetes.org.uk/Documents/nhs-diabetes/footcare/footcare-for-people-with-diabetes.pdf

5

Standard care doesn’t suffice for many patients

-

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100

Weeks

Persistency, % venous leg ulcers remaining unclosed1

-

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100

0 20 40 60 80 100

Weeks

Persistency, % diabetic foot ulcers remaining unclosed1

Source: 1 Rippon et al Wounds UK, 2007, Vol 3, No 2, reviewing 33 longitudinal studies of patients receiving standard care (compression) for venous leg ulcers, 2 Robertshaw (2001) Audit of time taken to heal diabetic foot ulcers, Practical Diabetes Int 2001 18(10) 6-9; 3 Jeffcoate, Keith G Harding (2003 ) Diabetic foot ulcers. THE LANCET Published online February 25; 4 Akhtar SchaperApelqvist Jude (2011) A review of the Eurodiale studies What lessons for diabetic foot care?. Curr Diab Rep. Red colour indicates studies with outcome data for six months or longer. Copyright infirst HEALTHCARE, reproduced with permission.

30% of venous leg ulcers do not heal within 6 months despite standard care1

25% of diabetic foot ulcers do not heal within 6 months despite standard care 2,3,4

6

Content






7

Healing requires addressing key elements for success

1 Winter (1978). Oxygen and Epidermal Wound healing; Advances in Experimental Medicine and Biology; Volume 92; 1978; pp 673-678; 2 Schreml et al.(2010); Oxygen in Acute and Chronic Wound Healing; The British Journal of Dermatology. 2010;163(2):257-268; Photo licenced under creative commons. Copyright infirst HEALTHCARE, reproduced with permission.

Oxygen is important for successful healing 1,2

■ Cell proliferation

■ Bacterial defence

■ Angiogenesis

■ Collagen synthesis

In the absence of oxygen several crucial processes stop working.

WOUND HEALING

Oxygen

Debridement & off-loading

Moist wound environment

Infection control

8

No oxygen – No healing

Delayed healing

Regional perfusion index1

Normal healing

0% 20% 40% 60% 80% 100%

58%(n=38)

3% (n=64)

95% (n=64)

Healed2Healing outcomes, % of wounds

Healing fails

Healing delayed

Normal healing

-60% (0.40)

- 40% (0.60)

Normal (1.00)

1Regional perfusion index – oxygen levels in wound vs oxygen levels in upper-body skin; 2 Hauser CJ. Tissue salvage by mapping of skin surface transcutaneous oxygen tension index. Arch Surg1987; 122: 1128-30. Copyright infirst HEALTHCARE, reproduced with permission.

Oxygen concentration in the tissue

… Yes oxygen – Yes healing

2%

28%

70%

100%

Very low Low/Impaired Near normal

98% of Healed ulcers

All healing ulcers

90 15 24<20mmHg* 20-40mmHg* >40mmHg*

222 61 85<0.40 RPI** 0.4-0.6 RPI** >0.6 RPI**

9

Yes oxygen – Yes healing

1 Hauser (1987) Tissue salvage by mapping of skin surface transcutaneous oxygen tension index. Arch Surg; 122: 1128-30; *Transcutaneous oxygen pressure; ** Regional perfusion index – oxygen levels near wound vs oxygen levels in upper-body skin; 2 Runagsetakit Chinsakchai Mahawongkajit et al (2010) Transcutaneous Oxygen tension predictor of ulcer healing in limb ischemia. JWC 19; Copyright infirst HEALTHCARE, reproduced with permission.

No oxygen – No healing…

70%

27%

3%

100%

Very low Low/Impaired Near normal

97% of Non-healing ulcers

All non-healing ulcers

1313 0 26<20mmHg* 20-40mmHg* >40mmHg*

1662 3<0.40 RPI** 0.4-0.6 RPI** >0.6 RPI**

81

2

1

2

1

0

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40

60

80

100

120

10 100 1000

µm

of

liqu

id f

ilm

Diffusion speed Vdif (µm/s)1

10

Despite plenty of oxygen in air, it is not available to the wound

1 Einstein-Smoluchowski-relation for water, infirst HEALTHCARE, Data on File March 2015; Pictures used with permission; Copyright infirst HEALTHCARE, reproduced with permission.

A liquid film of as little as 0.1mm blocks 99% of oxygen diffusion vs one micrometre1

-99%

Dif

fusi

on

gap

11

Three options for improved oxygen delivery

Sources: 1. Dissemond, Kröger, Storck, Risse, Engels (2015) Topical oxygen wound therapies for non-healing wounds, a review, JWC 24(2); | 2. Gordillo Sen et al (2009) Evidence based recommendations for the use of topical oxygen therapy. Int J Low Extrem Wounds. 2009 June ; 8(2): | 3. MIB11 Oxyzyme and Iodozyme 2-layer hydrogel wound dressings with iodine for treating non-healing wounds https://www.nice.org.uk/advice/mib11/chapter/summary | 4. Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE. Hyperbaric oxygen therapy for non-healing wounds. Cochrane Database of Systematic Reviews 2012, Issue 4 “More trials are needed to properly evaluate HBOT in people with non-healing wounds” | 5. Boundless. “Transport of Oxygen in the Blood.” Boundless Biology. Boundless, 14 Nov. 2014.; Pictures used with permission / Licenced under creative commons,. | 6. Arenberger, Elg, Cutting (2014) Topical haemoglobin – High potential for improved outcomes in non-healing venous leg ulcers based on post hoc analysis and simulation of wound closure outcomes. Poster presented at Wounds UK. Nov10-12 2014. | 7. Arenbergerova et al (2013) Effect of topical haemoglobin on venous leg ulcer healing. EWMA J 13 (2) | 8.Engels (2014) in Vitro oxygen binding test of oxygen. Peter Engels 09.04.14. Data on File. Copyright infirst HEALTHCARE, used with permission.

Hyperbaric oxygen therapy

Improves amount of oxygen in air and in blood plasma while in the chamber

But most of the oxygen in blood is not carried in the plasma5

Positive results but systematic review suggest data is weak4

Topical oxygen therapy

High concentration of oxygen delivered topically as gas or chemically1

Positive results but a systematic review2 and a recent NICE review of a new oxygen dressing found little proven benefit3

Facilitated diffusion

Haemoglobin, a natural oxygen transporter5 which increases oxygen in the wound bed

Applied with dressing changes it keeps working for days8

Few studies but highly positive, up to 2x standard care response rate 6 and pain scores <50%7

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://project3x5.tumblr.com/post/21102249535/hbot-into&ei=2EouVd3cEon1avHCgcAF&bvm=bv.90790515,d.d2s&psig=AFQjCNHqPd_U9fsmFqriTgmlpzoOX5nQ9A&ust=1429183514728779

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://project3x5.tumblr.com/post/21102249535/hbot-into&ei=2EouVd3cEon1avHCgcAF&bvm=bv.90790515,d.d2s&psig=AFQjCNHqPd_U9fsmFqriTgmlpzoOX5nQ9A&ust=1429183514728779

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://healthcareessentialsinc.com/staff/product-1/&ei=fkouVfDWN5bvaIHNgJgD&bvm=bv.90790515,d.d2s&psig=AFQjCNEr-MqS06oVxPc8XiVx_r7sMcnJZg&ust=1429183459827879

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://healthcareessentialsinc.com/staff/product-1/&ei=fkouVfDWN5bvaIHNgJgD&bvm=bv.90790515,d.d2s&psig=AFQjCNEr-MqS06oVxPc8XiVx_r7sMcnJZg&ust=1429183459827879

12

You can get it in a can - Granulox® haemoglobin spray

Granulox® is a medical device for the treatment of chronic wounds such as venous leg ulcers, arterial leg ulcers, mixed leg ulcers, diabetic foot ulcers, secondary healing of surgical wounds and pressure sores

Granulox® provides the wound with the required oxygen by means of diffusion. The active substance haemoglobin supplies the base of the wound externally with oxygen. The improved oxygen supply to the base of the wound supports wound healing.

- Hälsa Pharma GmbH. Granulox® Instructions for Use. April 2014

Pictures copyright SastoMed GmBH, reproduced with permission.

13

In vitro research shows diffusion rates increases by over 800%

1 Scholander (1960) Oxygen Transport through Hemoglobin Solutions. Science. Vol 131 585-590; 2 Engels (2014) in Vitro oxygen binding test of oxygen. Peter Engels 09.04.14. infirst HEALTHCARE, Data on File. 3 Hälsa Pharma GmbH. Granulox® Instructions for Use. April 2014; Spray can copyright SastoMed GmbH, reproduced with permission; Copyright infirst HEALTHCARE, reproduced with permission.

1x 8x

Transports more than eight times more oxygen at low oxygen tension1

Proven to work continuously for 5 days in vitro2

Apply when changing dressing, at least every three days3

H2O

Haemoglobin

Air Air

O2

14

Granulox®

Source: J. Lehy, I. Stoffels, J. Dissemond, J. Klode (2014). Photo-optoacoustic tomography of chronic wounds before and after treatment with a new hemoglobin spray (Granulox). Reproduced with permission.

HbO2

Before

20 minutes after Granulox® application

Hb

- Oxygen delivered within 20 minutes

15

Content






16

Two prospective randomised control studies

Tamaulipas study1 Prague study2,3

Design • Prospective randomised single centre study in chronic venous leg ulcers (ABI>0.8)

• 2x36 pts standard care plus sham product vs standard care plus Granulox, 13 weeks

• Assessor blinded.

• Prospective randomised single centre study in chronic lower leg ulcers

• 2x14 pts; Standard care vs Granulox treatment, 6 months plus switch-over follow-up

• Un-blinded

Sources: 1Arenberger, Engels, Arenbergerova, Gkalpakiotis, García, Martínez, Anaya, Fernandez (2011). Clinical results of the application of a hemoglobin spray to promote healing of chronic wounds. GMS Krankenhaushygiene Interdisziplinär 2011, Vol. 6(1), ISSN 1863-5245; 2Arenberger, Elg, Cutting (2014). Topical haemoglobin – High potential for improved outcomes in chronic venous leg ulcers based on post hoc analysis and simulation of wound closure outcomes. Poster presented at Wounds UK Nov10-12 2014. 3Arenbergerova et al (2013) Effect of topical haemoglobin on venous leg ulcer healing. EWMA JOURNAL VOL 13. NO 2., n=72;

-

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100

- 26% better

17

Tamaulipas: Granulox® 93% healed vs 7% at 6 months*

Weeks

Wound persistency, % remaining unclosed1 and the results from the Gobierno de Tamaulipas study2

* Results from the Gobierno de Tamaulipas study (n=28; 14 Granulox ® (93% wound closure) + 14 standard care (7% wound closure) plotted as starting in a chronic patient population as predicted bythe studied reported by Rippon et al. 1 Rippon, Davies, White, Bosanquet (2007). The economic impact of hard to heal leg ulcers. Wounds UK. Vol 3, No 2.; 2 Arenberger, Engels, Arenbergerova, Gkalpakiotis, García, Martínez, Anaya, Fernandez (2011). Clinical results of the application of a hemoglobin spray to promote healing of chronic wounds. GMS Krankenhaushygiene Interdisziplinär 2011, Vol. 6(1), ISSN 1863-5245 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252654/pdf/KHI-06-05.pdf). Copyright infirst HEALTHCARE, reproduced with permission.

Representative chronic wound population receiving standard care1

Representative chronic wound population receiving standard care1

overlaid with healing outcomes (93% vs 7%) from Tamaulipas chronic lower leg ulcer study at 6 months2

28% -

18

Prague study

Tamaulipas study1 Prague study2,3

Design • Prospective randomised single centre study in chronic venous leg ulcers (ABI>0.8)

• 2x36 pts standard care plus sham product vs standard care plus Granulox, 13 weeks

• Assessor blinded.

• Prospective randomised single centre study in chronic lower leg ulcers

• 2x14 pts; Standard care vs Granulox treatment, 6 months plus switch-over follow-up

• Un-blinded

1Arenberger, Engels, Arenbergerova, Gkalpakiotis, García, Martínez, Anaya, Fernandez (2011). Clinical results of the application of a hemoglobin spray to promote healing of chronic wounds. GMS Krankenhaushygiene Interdisziplinär 2011, Vol. 6(1), ISSN 1863-5245; 2Arenberger, Elg, Cutting (2014). Topical haemoglobin – High potential for improved outcomes in chronic venous leg ulcers based on post hoc analysis and simulation of wound closure outcomes. Poster presented at Wounds UK Nov10-12 2014. 3Arenbergerova et al (2013) Effect of topical haemoglobin on venous leg ulcer healing. EWMA JOURNAL VOL 13. NO 2., n=72;

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

0 2 6 13

Standard care plus GranuloxStandard care alone

19

Patient quality of life significantly better by week two

1 Adapted from Arenbergerova et al (2013) Effect of topical haemoglobin on venous leg ulcer healing. EWMA JOURNAL VOL 13. NO 2., n=72 ; *-68% and -7% reported in the paper, slightly different results compared to those extracted from reading scores from the graphics in the paper. Copyright infirst HEALTHCARE, reproduced with permission.

Mean pain scores, 10 cm VAS1

-33%

-46%

-68%

2%

-4%-7%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

10%

Standard care plus Granulox

Standard care alone

Week 2

Mean pain score reduction %1

Week 6 Week 13*

Week

20

100% response rate, 0% worsening, by week four

1 Adapted from Arenbergerova et al (2013) Effect of topical haemoglobin on venous leg ulcer healing. EWMA JOURNAL VOL 13. NO 2., n=72, responder data provided courtecy of Dr Peter Arenberger, post hoc analysis. Infirst HEALTHCARE Data on File March 2015 (unpublished, submitted for publication to Journal of Wound Care). Copyright infirst HEALTHCARE, reproduced with permission.

48% 48%

35%

100%94% 97%

Week 4 Week 8 Week 13

Percent responders

-52% -48%

-65%

0%

-6% -3%

Standard care

+ Granulox

Week 4 Week 8 Week 13

100% of patients in the Granulox arm responding and showing a wound size reduction at 4 weeks, vs 48% under standard care

Percent of patients worsening (wound size increase)

Avoiding risk of deterioration, no Granulox patient worsening, 52% of standard care patients continuing to deteriorate

Improved vs worsened at week 132

35%

-65%

97%

-3%

Standard care

+ Granulox

Percent improved (wound size reduction)

Percent worsened (wound size increase)

21

53% average size reduction and 97% improved by week 13

1 Adapted from Arenbergerova et al (2013) Effect of topical haemoglobin on venous leg ulcer healing. EWMA JOURNAL VOL 13. NO 2., n=72, 2 Responder data provided courtecy of Dr Peter Arenberger, post hoc analysis. Infirst HEALTHCARE Data on File March 2015 (unpublished, submitted for publication to Journal of Wound Care). Copyright infirst HEALTHCARE, reproduced with permission.

21.3%

-53.4%

-70%

-50%

-30%

-10%

10%

30%

50%

70%

0 2 4 6 8 10 12 14 16

Standard care

Standard care plusGranulox

95% Confidence intervals

Percent wound size change vs baseline1

74% difference in average baseline adjusted wound size change

Worsened

97% improved

22

Three retrospectively controlled studies

Diabetic Foot Ulcers1 Chronic Wounds2 Sloughy wounds3

Study designs

• Retrospectively controlled single centre study in UK

• 2x50 pts; Granulox prospective treatment, vs Standard care retrospective from same clinic and period the year before

• All wounds with <40% wound-size reduction over last 4 weeks, first 50 patients seen meeting inclusions, 6 months follow-up, exclusions as per labelling

• Un-blinded



• SINBAD ≤2, Chronic for min 12 weeks, 6 months follow-up. First 20 patients seen meeting inclusions, exclusions at baseline as per Granulox labelling

• Un-blinded



• All wounds ≥10% slough coverage at baseline, first 100 patients seen meeting inclusion, 6 months follow-up, exclusions as per label

• Un-blinded.

• Chronic DFUs• 20 Standard Care• 20 As above + Granulox®

• Chronic Wounds • 50 Standard Care• 50 As above + Granulox®

• Sloughy Wounds• 100 Standard Care• 100 As above + Granulox®

1 Data shared by Sharon Hunt ahead of publication, data on file, preliminary pending publication, July 2016; 2 Data shared by Sharon Hunt ahead of publication, data on file, preliminary pending publication, July 2016; 3 Data shared by Sharon Hunt ahead of publication, data on file, preliminary pending publication, July 2016.

-12%-14%

-41%

-52%

-63%-67%

-75%-73%

-87%

-92%-94% -93%

-91%-89%

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

4 8 12 16 20 24 26

ControlGranulox

-26%

-39%-37%

-43%

-53%

-58%

-63%-63%

-78%

-89%-91%

-96% -96% -95%-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

4 8 12 16 20 24 28

Control

Granulox

23

Substantially faster and greater wound size reduction

Chronic Diabetic Foot Ulcers Chronic Wounds – Any Slough Woundsn=20+20 n=50+50 n=100+100

Average percent wound-size reduction vs baseline, by week

Source: Sharon Hunt, Data on File, Preliminary pending data validation and publication

Three patients stopped Granulox early at week 12 (G34), week 16 (G27) and week 20 (G17) and all three deteriorated, two patients G20 and G45 stopped just before healed

Reduction contributed from two wounds that stopped Granuloxand started to deteriorate (S91 Week 10; S83 Week 16, E19 Week 20)

Week Week Week

Three wounds stopping treatment with Granulox and subsequently stagnated or worsened (Pt6, Pt7, Pt11)

Pending

-27%

-32%

-57%

-63%

-68%-71%

-74%

-87%

-93%-96% -97% -98% -98% -98%-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

4 8 12 16 20 24 26

Control Granulox

44%

29%

17%

8%6% 5% 5% 5%

57%

1% 0% 0% 0% 0% 1% 1%

0%

10%

20%

30%

40%

50%

60%

0 4 8 12 16 20 24 26

Control

Granulox

38%

32%

26%

11%

6%4% 4% 4%

47%

0% 0% 0% 0% 0% 1% 1%

0%

10%

20%

30%

40%

50%

60%

0 4 8 12 16 20 24 28

Control

Granulox

50%

40%

24%

19%17%

14%

11%9%

50%

0% 0% 0% 0% 0% 1% 1%

0%

10%

20%

30%

40%

50%

60%

0 4 8 12 16 20 24 28

Control

Granulox

24

Rapid and reliable elimination of Wound SloughSlough-elimination within four weeks. Slough return only when Granulox was stoppedAverage percentage of sloughy tissue coverage, % - for wound remaining open only

Base; All valid data per period. Healed wounds treated as zero slough.

Base; All valid data per period. Healed wounds treated as zero slough. * Two more patients stopped Granulox just before full healing G20 & G45 - with no slough recurrence.


Base; All valid data per period. Healed wounds treated as zero slough.

6 wounds remaining in the Granuloxgroup, 4 with slough, with these no longer receiving Granulox. Of the 6 patients where Granulox was stopped pre-maturely, slough re-occurred in 4 patients, but in no wounds treated with Granulox.

Week Week Week

Chronic Diabetic Foot Ulcers Chronic Wounds – Any Slough Woundsn=20+20 n=50+50 n=100+100

Three patients stopped Granuloxpre-maturely* at week 12 (G34), week 16 (G27), and 20 (G17) subsequently all three recurred with slough – with no slough returning in any other Granulox treated wounds.

Where Granulox is stopped early (Pt6, Pt7, Pt11), slough may return (Pt6 only)

Pending

32

7

50

19

0

10

20

30

40

50

60

70

80

90

100

0 4 8 12 16 20 24 28

ControlGranuloxMax

21

4

33

9

0

5

10

15

20

25

30

35

40

45

50

0 4 8 12 16 20 24 28

ControlGranuloxMax

17

11

12

4

17

8

0

2

4

6

8

10

12

14

16

18

20

0 4 8 12 16 20 24 28

ControlGranuloxMax Delta

25

Twice as many wounds fully closed within 8-16 weeks

Chronic Diabetic Foot Ulcers Chronic Wounds – Any Sloughy Wounds

*One death in each of the groups, week 6 in the control group, and week 10 in the Granulox group, excluded

**Six deaths occurred in the Control group during the follow-up period, One death in the Granulox group, additionally four patients were lost to follow-up in the control group. To ensure conservative analysis only patients completing follow-up included.

n=20+20* n=50+50**

***Five deaths occurred in the Control group during the follow-up period, no deaths occurred in the Granulox group. No patients were lost to follow-up

n=100+100***

Number of wound non-healed by week – Wound closure defined as complete wound epithelialisation

A substantial difference in healing outcomes already within 8-10 weeks


53% fewer wounds remaining by week 16



Pending

3.4

1.9

1.0

0.40.2 0.2 0.2 0.1

6.2

0.6

0.30.1 0.1 0.2 0.2 0.2

0

1

2

3

4

5

6

7

0 4 8 12 16 20 24 26

Control

Granulox

3.2

2.8 2.9

1.3

0.8

0.3 0.3 0.3

4.6

0.7

0.1 0.2 0.2 0.2 0.2 0.2

0

1

2

3

4

5

6

7

0 4 8 12 16 20 24 28

Control

Granulox

3.6

2.5

1.41.2 1.2

0.7 0.7

0.4

4.1

0.30.1 0.0 0.0 0.0 0.0 0.0

0

1

2

3

4

5

6

7

0 4 8 12 16 20 24 28

ControlGranulox

26

Quickly improved quality of life, pain reduction within a week

Average reported pain scores (10 cm VAS)

Source: Sharon Hunt, Data on File, Preliminary pending data validation and publication; * Average pain-scores across all patients, healed wounds recorded as zero pain

Diabetic Foot Ulcers Chronic Wounds Sloughy Woundsn=20+20* n=50+50* n=100+100*

-97%

-95%

About half of DFU patients are neuropathic and therefore have no or minimal pain

-73%

Average pain-scores are 73-97% lower for Granuloxpatients, despite starting higher

Pending

26

WeekWeek Week

5

0

8 8

1

0 0 00

1

2

3

4

5

6

7

8

9

Death Amputation Surgery(theatre/bedside)

Infected/Antibiotics

Control

Granulox

5

0

14

3

0 0

1 1

0

2

4

6

8

10

12

14

16



Control

Granulox

27

Much fewer complications requiring antibiotics or surgery

*Control; Death (A08), Amputation (A20, A11 awaiting amputation but not within 28 week follow-up), Theatre Surgery (A10, A18, A20), Bedside surgery (A04, A08, A15), Infection/Anti-biotics (A04,A11,A14,A15,A18); Granulox; Death (Pt10) ; ** Control; 6 Deaths (C04, C09, C18,C20,C27, C46); 8 surgery (C05,C12,C13,C14,C20,C25,C36,C44), 8 infection/Anti-biotics (C11,C12,C20,C21,C23,C30,C41,C50), 5 lost to follow-up (C22,C23,C24, C25); Granulox, One death (G07). *** Control; 5 deaths (R20,R33,66,68,78); 14 surgery (R09, R28, R31, R41, R51, 55, 60, 70, 73, 74, 82, 90, 92, 94), 3 infected/Antibiotics (R10, R12, 92); Granulox One surgery (S91), and one infection (S90).

Diabetic Foot Ulcers* Chronic Wounds** Sloughy Wounds***n=20+20 n=50+50 n=100+100

Number of patients Number of patients Number of patients

1 1

6

5

1

0 0 00

1

2

3

4

5

6

7

8

9



Control

Granulox

Pending

Number of recorded adverse events by treatment group

28

Content






29

In fifteen years and more than one hundred evaluations….

“In fifteen years as a health economist at the Centre for Health Economics at York,as a director of Pharmerit Ltd UK and as an NICE Scientific Advice Programme expertand having analysed, constructed or reviewed over 100 cost-effectiveness /economic evaluation studies I cannot recall a single technology that demonstratesas much cost-effectiveness potential as Granulox”*

- Chris Bojke, Senior Research Fellow, Centre for Health Economics, University of York

* Bold emphasis added; reproduced with permission.

Twice as cost effective vs other wound-care – As assessed in Germany

“From an economic point of view, the Granulox® combination treatment is superior to all other alternative treatments tested”

- Professor Wilfred van EiffCentre for Hospital Management

Westphalian Wilhelms University of Munster

Treatment utility per unit cost (index)1

1 Infirst Healthcare Data on File. Treatment utility per unit cost calculated based on treatment utility / total cost of treatment per episode. Treatment utility per unit cost calculated from the utility scores and total episode treatment costs for each treatment type and normalised based on standard care utility as reported by von Eiff (2013). Health economic evaluation. The economic efficiency of Granulox. Centre for Hospital Management. Westphalian Wilhelms University of Munster.

15.5

27.8

Hydroactive Granulox

30

0.40.3

-0.1

0.7

0.4

-0.3-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

Standard(6 mo)

Plus Granulox(6 mo)

Saving(at 6 mo)

Standard(12 mo)

Plus Granulox(12 mo)

Saving(at 12 mo)

Wee

ks o

f w

ou

nd

car

e (o

pen

w

ou

nd

wee

ks)

Mill

ion

s At six months At twelve months

31

Simulated cost savings may add up to more than R1Bn per year

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 13 26 39 52

Per

cen

t ch

ron

ic V

LU w

ou

nd

s re

mai

nin

g u

n-h

eale

d

Weeks

Granulox

Non-Granulox

26 weeks (6 months)

Simulated wound persistency1

1 Adopted from Arenberger Elg Petyt Cutting (2014). Expected outcomes from topical haemoglobin spray in non-healing and worsening venous leg ulcers, J Wound Care 24(5), projected to estimated chronic VLU population of 15,000 in south Africa; 2Applying average weekly cost of care from Harding, Posnett and Vowden (2013) and projected to YE2014 using PSSRU Unit Costs HCHSpay and prices index and converted to South African Rand at 20:1; Costs: Healed R137pw, Improving/progressing R1999pw, Static/stagnant R2282pw, Deteriorating R3629pw (No patients assumed severe at R14,500pw). Costs of Granulox® assuming R153.5 per application, 30 applications/can and mean of 2.33 applications per week per patient for an additional weekly cost of R357.7/week.

When projected to 15,000 chronic VLUs1

1,200

796

-404

2,343

1,083

-1,260-1,500

-1,000

-500

-

500

1,000

1,500

2,000

2,500

3,000

Standard(6 mo)

Plus Granulox(6 mo)

Saving(at 6 mo)

Standard(12 mo)

Plus Granulox(12 mo)

Saving(at 12 mo)C

ost

of

wo

un

d c

are

(ZA

R)

Mill

ion

s

32

Three retrospectively controlled datasets with activity level data

Diabetic Foot Ulcers1 Chronic Wounds2 Sloughy wounds3

Study designs

• Chronic DFUs• 20 Standard Care• 20 As above + Granulox®

• Chronic Wounds • 50 Standard Care• 50 As above + Granulox®

• Sloughy Wounds• 100 Standard Care• 100 As above + Granulox®

1 Persistent for min 12 weeks, SINBAD ≤2, exclusions as per label; 2<40% wound size reduction over last 4 weeks, exclusions as per label; 3 ≥10% slough coverage at baseline, exclusions as per the label.

• Dressings used• Wound rinse used, if any• Debriding agents used, if any• Weekly dressing frequency• Number of nurse visits by type• Surgical procedures at tariff prices• Prescription items specific for wound

care, i.e., antibiotics, pain relievers.

• Offloading devices not included unless fitted during the follow-up period.







Data available

33

The method used to convert to South African technology impact

- Actual dressings and health care resources used in each of the evaluations from case records

- Costs of dressings, nurse visits and surgical procedures extracted from UK Tariff

- Prices converted to South African Rand based on long-term exchange rate and South African usage*

* All prices for dressings and healthcare resources assumed at current UK tariff prices and GBP/Rand FX rate of £1 = R20.0. The price of Granulox® is assumed at R153.5 per application (30 applications net per 12ml spray can (R4,605 equivalent) all net VAT. Graphics used with permission / Under permissible use.

1 2 3

Steps taken to convert international data to cost effectiveness data for use in South Africa

https://en.wikipedia.org/wiki/File:Adhesive_dressing-20100202.jpg

https://en.wikipedia.org/wiki/File:Adhesive_dressing-20100202.jpg

R39,556

R18,450

R38,996

R19,754

R1,864

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000

160,000

Control Granulox Savings

Wk0-26 Wk27-52

R62,903

R25,728

R52,523

R21,866

R6,518

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000

160,000


Wk0-26 Wk27-52

R98,931

R35,747

R95,588

R35,101

R2,696

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000

160,000


Wk0-28 Wk29-52

34

Granulox® consistently reduce total cost of care by half

Average total cost of care from baseline including costs of surgical procedures for the first 26/28 weeks, but no costs of surgery from week 26/28 onwards1

1 Method to predict time to wound closure used as per Arenberger, Cutting, Elg, Petyt (2015) Expected outcomes from topical haemoglobin spray in non-healing and worsening venous leg ulcers. J Wound Care. May;24(5):228, 230-2, 236. Costs include wound rinse, primary and secondary dressings, nursing, prescriptions relating to the wound, and the cost of any wound-related surgical procedures during the follow-up period. Same wound care regimen as last observed assumed continued for extension. No cost of prescriptions or surgery assumed for the period from week 27/29-52. 2 In DFUs, data for patients who died or were lost to follow-up included up to the date of amputation, loss of follow up or death with no cost assumed from amputation or death. In the control cohort, one death week 6 and one amputation week 7 with the cost of the amputation included for cost of surgery. 3 In the Chronic control cohort, there were 6 deaths, wk 2, 8, 9, 3x10, and 4 patients lost to follow-up (All in wk8, records no longer available, C22, C23, C24, C25). Data for patients who died or were lost to follow-up included up to the date of amputation, loss of follow up or death with no cost assumed from amputation or death . 4 In the Slough dataset control group, there were 5 deaths (wks 3,5,10,11,12). There were no deaths in the Granulox group. For patents who died, healing rate to date of last observation used as basis to predict time to wound closure should the patient have not died. No procedure or prescription costs assumed for the period 27/29-52. Data by Sharon Hunt / South Tees NHS Foundation Trust. Preliminary pending validation and publication.

71% reduction in total cost of care

Costs of care, 52 weeks, R/patient2 (n=40)



Costs of care, 52 weeks, R/patient3 (n=100) Costs of care, 52 weeks, R/patient4 (n=200)

Diabetic Foot Ulcers Chronic Wounds Sloughy wounds

Pending

R35,910R42,879

R4,605

R32,254

R32,233

R0

R20,000

R40,000

R60,000

R80,000

R100,000

R120,000

Actual price Ex Surgerysavings

Inc Surgerysavings first 26

weeks

26 weeks Week 27-52, additional

R55,798R67,661

R4,605

R22,803

R22,307

R0

R20,000

R40,000

R60,000

R80,000

R100,000

R120,000



weeks


R54,919

R72,101

R4,605

R34,148

R34,053

R0

R20,000

R40,000

R60,000

R80,000

R100,000

R120,000



weeks


35

The fair price per can of Granulox® is R73-106k per can

Fair price per can analysis - Average total cost of care savings per can of Granulox used – as estimate of cost neutral price of a can of Granulox®1

1 Total savings in patient care divided by the number of cans based on per spray basis, i.e. the same can is used on multiple patients. Time to healing method used as per Arenberger, Cutting, Elg, Petyt (2015) Expected outcomes from topical haemoglobin spray in non-healing and worsening venous leg ulcers. J Wound Care. May;24(5):228, 230-2, 236. Costs include wound rinse used, primary and secondary dressings, nursing, prescriptions relating to the wound, and the cost of any wound-related surgical procedures during the follow-up period based on UK tariff prices and a Rand/GBP exchange rate of 20. Same wound care regimen as last observed assumed continued for wounds remaining unhealed at 6 months and also from death onwards in slough dataset. No cost of prescriptions or surgery assumed for the period from week 27/29 to 52. 2 In DFUs, data for patients who died or were lost to follow-up are included up to the date of amputation, loss of follow up or death with no cost assumed from amputation or death. In the control cohort, one death week 6 and one amputation week 7 with the cost of the amputation included for cost of surgery. 3 In the Chronic control cohort, there were 6 deaths, wk 2, 8, 9, 3x10, and 5 patients lost to follow-up (All in wk8, records no longer available). Data for patients who died or were lost to follow-up included up to the date of amputation, loss of follow up or death with no cost assumed from amputation or death. 4 In the Slough dataset control group, there were 5 deaths (wks 3,5,10,11,12). There were no deaths in the Granulox group. For patents who died, healing rate to date of last observation used as basis to predict time to wound closure should the patient have not died. Note: Preliminary pending validation and publication. Data by Sharon Hunt / South Tees NHS Foundation Trust.

Diabetic Foot Ulcers Chronic Wounds Sloughy wounds

The actual justified price of Granulox® is at least 23 timeshigher than the current price a 96% discount vs fair price

Savings per can – Value realised per can3Savings per can – Value realised per can2 Savings per can – Value realised per can4



Pending

R75,112R89,968

R106,155

36

Content





- Sensitivity analysis – Assessment of robustness of effectiveness across patient sub-populations

37

Few baseline differences can have influenced results

Tests for difference in baseline patient and wound attributes between control and Granulox® groups by evaluation dataset

0 0.2 0.4 0.6 0.8 1

Age

HbA1c

Healing rate

History

Neuropathy

Off-loading

SINBAD

Ulcer type

Vascular

Wound size

p-value Critical (p<0.05)

Source: Data on File, shared by Sharon Hunt / South Tees NHS Trust ahead of publication. All categorical data analysis using Chi-square, and all parametric data analysed using two-tail, different variance t-tests. Data included for all patients regardless of death or drop-out on intention to treat basis.

DFU wounds – p-values from ttests or chi-square tests between groups (n=40), note small samples

Chronic wounds – p-values ttest/chi-square (n=100), note small counts for some ulcer sub-types

Slough study – p-values ttest for parametric variables and chi-square for nominal data (n=200)

0 0.2 0.4 0.6 0.8 1

Age

HbA1c

Healing rate

History

Neuropathy

Off-loading

SINBAD

Ulcer type

Vascular

Wound size


More very big wounds in the control group

0 0.2 0.4 0.6 0.8 1

Age

HbA1c

Healing rate

History

Neuropathy

Off-loading

SINBAD

Ulcer type

Vascular

Wound size


More ischemic wounds in control

More neuropathic wounds in the control

More deteriorating wounds in Granulox group

Smaller average wound size in Granulox group

More wounds with shorter wound persistence in the Granulox group

Pending

38

Wound healing effectiveness at 4 weeks selected for analysis

While any other measures for estimating impact on wound healing from variations in baseline attributes would be possible, wound size reduction from baseline to week 4 was selected2.

1 Chadwick, P., McCardle, J. et al (2015). Appropriate use of topical haemoglobin in non-healing wound management: consensus recommendations. Wounds UK, EWMA Special.; 2Analysis of additional outcome variables can be conducted on request, e.g. wound closed at 6 months, total cost of care excluding surgical procedures, total cost of care including surgery, 12 months predicted costs.

Patient with non-healing wound referred for specialist/MDT care

Holistic and specific assessment

Standard care (4 weeks)

Is the wound healing?

Yes No

Continue care plan and reassess as appropriate

Reassessment by specialist every 4 weeks

Persistent non-healingRefer for specialist/MDT assessment (e.g. vascular)

in line with national guidelines

Clinical signs of infectionNo Yes

Antimicrobials as per local protocol

Topical haemoglobin

Healing at 4-Weeks - suggested as the period for review of effectiveness in the Granulox® consensus guidelines1

Substantial and consistent supportive data - culminating in international guidance

- Bulstrode, Goode, Scott (1987). Measurement and prediction of progress in delayed wound healing. J R Soc Med. 80(4):210-2

- Kantor, Margolis, (2000). A multicentre study percentage change in venous leg ulcers as a prognostic index of healing at 24 weeks. Br J Dermatol; 142(5):960-4

- Philips, Machado, Trout et al (2000). Prognostic indicators in venous ulcers. J Am Acad Dermatol 43(4):627-30

- Gelfand, Hoffstad, Margolis (2002). Surrogate endpoints for the treatment of venous leg ulcers. J Invest Dermatol, 119(6):1420-5

- Margolis, Gelfand, Hoffstad (2003). Surrogate end points for the treatment of diabetic neuropathic foot ulcers. Diabetes Care, 26(6):1696-700

- Sheehan, Jones, Caselli et al (2003). Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of healing in a 12-week prospective trial. Diabetes Care. 26(6):1879-82

- Steed, Attinger, Colaizzi et al (2006). Guidelines for the treatment of diabetic foot ulcers, Wound repair and regeneration 14(6): 680-92

-“if a reduction [in wound size] of at least 40% following 4 weeks of standard therapy is not seen, then treatment re-evaluation should ensue”

39

Evaluation of baseline differences

1. Differences in baseline wound size; Chronic and Sloughy wounds

2. The impact of wound ischemia; Sloughy wounds

3. The impact of wound neuropathy; Sloughy wounds

4. The impact of wound persistency prior to baseline; Chronic wounds

5. The impact of healing rate prior to baseline; Chronic wounds

40

Substantial healing benefit regardless of baseline wound size

Analysis of impact of difference in baseline wound size on healing outcomes – Wounds size change to Week 4

0 0.2 0.4 0.6 0.8 1

Age

HbA1c

Healing rate

History

Neuropathy

Off-loading

SINBAD

Ulcer type

Vascular

Wound size


25

16

8

27

18

5

0

5

10

15

20

25

30

0-10 10-100 >100

Control

Granulox

Source: Data on File, shared by Sharon Hunt / South Tees NHS Trust ahead of publication. Wound size at baseline calculated as L*W*π/4; 1 Excludes patient C4 in the control group, size 4.7cm2 (RIP week 2); *Note: Small sample size.

Nearly significant. More very large wounds in control group and more small wounds in Granulox® group

Chronic wounds – p-values for group differences by variable, focus on baseline wound size

-9%

-14%-16%

-73%-77%

-54%

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

0-10 10-100 >100

Control

Granulox

Chronic wounds – Observed healing rate from baseline to week four in the Granulox® treatment group and in the retrospective control cohort1

Chronic study – number of patients by baseline wound size1

Nearly twice as many very large wounds More than three times higher

average healing speed regardless of wound size

p=0.05

Wounds size in cm2

Wounds size at baseline in cm2

*

*

Pending

41

Benefit regardless of wound size also for sloughy wounds

To be completedBaseline wound size analysis – Variation in healing speed depending on baseline wound size

Source: Data on file. Shared by Sharon Hunt / South Tees NHS Foundation Trust, preliminary pending publication. Excludes one patient in the Control group, Patient 66, who died in Week 3, who had a large wound size area of 117cm2 at baseline.

Sloughy wounds – p-values for group differences by variable, focus on baseline wound size

0 0.2 0.4 0.6 0.8 1

Age

HbA1c

Healing rate

History

Neuropathy

Off-loading

SINBAD

Ulcer type

Vascular

Wound size


More small wounds in the Granulox group, and more very large wounds in the control group

39

2623

12

25

3028

16

0

5

10

15

20

25

30

35

40

45

0-5 >5-10 >10-40 >40

Granulox

Standard

Sloughy wounds1 – number of wounds by baseline wound size area at baseline in cm2

Baseline wounds size area, in cm2

Sloughy wounds – Analysis of baseline adjusted wound size change, in cm2, week 0 to week 4 (see lower graph for percent wound size change vs baseline)

Percent wound size change, Week 0-42

Consistent and substantial healing-benefit regardless of baseline wound size, with 20-70% greater wound size reduction at 4 weeks vs standard care alone, increasing with wound size

p=0.05

Baseline wounds size area, in cm2

Pending

-2.4-7.1

-16.2

-54.0

-0.5-4.2

-0.2

-18.8

-60

-50

-40

-30

-20

-10

0

0-5 >5-10 >10-40 >40

Granulox

Standard

-94% -91%

-82%

-69%

-26%

-57%

-4%-10%

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

0-5 >5-10 >10-40 >40

42







-36%

-90%

10%

-34%

-100%

-80%

-60%

-40%

-20%

0%

20%

Yes No

Granulox Standard

43

Substantial benefits also in non-ischemic wounds

To be completedImpact of ischemia analysis – Variation in healing speed depending on ischemic condition of patient

Source: Data on File. Shared by Sharon Hunt / South Tees NHS Foundation Trust; Data missing at week 4 for six patients; One for Standard Ischemic, patient 28 (missing data for week 4, later returned to care with size increased by 56% by week 8. Four in the Standard Non-Ischemic patients with missing data at week 4 – Patient 31, 51, 66 (RIP week 3), 82, 90. No missing data in the Granulox group. *Note: Very small sample size, n=5).

Sloughy wounds – p-values for group differences by variable, focus on vascular deficiency

0 0.2 0.4 0.6 0.8 1

Age

HbA1c

Healing rate

History

Neuropathy

Off-loading

SINBAD

Ulcer type

Vascular

Wound size


More wounds with vascular deficiency in the control group

5

95

17

83

0

10

20

30

40

50

60

70

80

90

100

Yes No

Granulox

Standard

Sloughy wounds – number of wounds diagnosed with vascular deficiency

Sloughy wounds – Average wound size change to week 4 by vascular deficiency status

Ischemic underlying disease condition

Ischemic underlying disease condition

*

Double the average healing speed across also non-ischemic wounds

p=0.05-46%

-56%

Pending

44







-11%

-90%

9%

-35%

-100%

-80%

-60%

-40%

-20%

0%

20%

Yes No

Granulox Standard

45

Substantial healing benefit regardless of neuropathy status

Impact of neuropathy analysis – Variation in healing speed depending on neuropathy of patients

3

97

19

81

0

10

20

30

40

50

60

70

80

90

100

Yes No

GranuloxStandard

*Note: Very small sample size, n=3.

More patients with neuropathy in the control cohort

Sloughy wounds – number of patients diagnosed with neuropathy

Diagnosed with Neuropathy

Sloughy wounds – p-values for group differences Sloughy wounds – Wound size change to week 4 by neuropathy status

Diagnosed with Neuropathy

More than double the average healing speed also in the non-neuropathic only group

*p=0.05

*

Pending

46







47

Healing impact is superior, regardless of wound persistency

Analysis of impact of wound persistence at baseline – Wound size change to week 4 by wound persistency at baseline

Source: Data on File, shared by Sharon Hunt / South Tees NHS Trust ahead of publication. Wound size calculated as L*W*π/4; 1 Excludes patient C4 in the control group, present for 1.4 months at baseline (RIP week 2).

Chronic wounds – p-values for pre-baseline wound persistence difference

More wounds with shorter persistency in the Granulox® cohort

Chronic wounds – plot of realised healing outcomes to week 4, as percent wound size reduction, by baseline wound persistence, in months1

R² = 0.269

-120%

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12

0

1619

74 4

2

34

6

24

2

0

5

10

15

20

25

30

35

40

0-1 1-2 2-3 3-4 4-6 6-10

ControlGranulox

Chronic wounds – Number of wounds by wound persistency at baseline, in months

Substantially more wounds with greater wound size reduction on Granulox® -regardless of wound history. Also, there may be a healing speed benefit from treating with Granulox® earlier rather than later

Wound persistency at baseline, in months Wound persistency at baseline, in months

Wound size area change, % vs baseline at week 4; Linear regression lines by group

p=0.05 Control

Granulox

Pending

48







-100%

-12%

-70% -70%

-91%

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

Improving Static Deteriorating

Control Granulox

1

49

03

40

7

0

10

20

30

40

50

60

Improving Static Deteriorating

Control

Granulox

49

Substantial benefit regardless of baseline healing trajectory

Healing trajectory analysis – Variation in healing speed depending on baseline healing speed (wound size change)

Note: * Very small sample (n=5, 5, 3 respectively). 1Excludes patient C4 in the control group (RIP Week2), in “Static” group. Samples <5 shaded. Data on File, shared by Sharon Hunt / South Tees NHS Foundation Trust ahead of publication. Preliminary pending publication.

Chronic wounds – p-values for group differences by pre-baseline wound size change

More deteriorating wounds in the Granulox group

Chronic wounds – wounds by healing rate in the four weeks prior to baseline

Wound healing trajectory at baseline, i.e. Size change <-5% Improving, +/-5% Static, >5%

Deteriorating

Chronic wounds – Healing rate from baseline to week four by group, by ingoing healing trajectory1

More than double the average healing speed regardless of prior ‘chronic’ healing trajectory

*

*

*

p=0.05

Pending

50

Thank you

Any questions, please contact Richard Straughan on [email protected]

PW0872016 v1.7 Sept 2016

mailto:[email protected]



Case series show excellent results across all indications

51

52

Essential product information*

Source: *Hälsa Pharma GmbH. Granulox® Instructions for Use. April 2016

53

Essential product information continued and Pack design*

Source: *Hälsa Pharma GmbH. Granulox® Instructions for Use. April 2016