A breakthrough in the management of neuro- ischaemic

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A breakthrough in the management of neuro-ischaemic diabetic foot ulcers

Declaration of

Financial Interests or Relationships

Speaker Name: Emilio Galea

I have the following financial interest or relationship(s) to disclose with regard to the subject matter of this

presentation:

• I derive an income from URGO Medical associated with this presentation

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Outcomes in Neuroischemic versus Neuropathic Diabetic Foot Ulcers

• DFU patients with ischemic or neuro-ischemic disease have a much higher probability of amputation

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INFECTION MANAGEMENT

VASCULAR ASSESSMENTDEBRIDEMENT / HYPERKERATOSIS

REMOVAL

OFF-LOADING

EFFECTIVE LOCAL TREATMENT(EVIDENCE BASED MEDICINE)

Standard of Care (SOC) of DFU is based on…

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Published in the

Journal of Wound Care

Vol 22. Iss. 2, Feb 2013,

78 – 81. D.R. Shanahan

1.D.R. Shanahan. Journal of Wound Care: The Explorer Study: the first double-blind RCT to assess the efficacy of TLC-NOSF on DFUs The Vol 22. Iss. 2, Feb 2013, 78 – 81. 2.European Medicines Agency, Science Medicine Health, January 2013

[1]

Published in the

European Medicines Agency

Jan 2013[8]

…might be regarded as a major therapeutic progress.

…makes this an ambitious, double-blind,randomised controlled trial.

A HIGHLY ANTICIPATED CLINICAL TRIAL

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A European collaboration to build the Protocol:the Explorer Board

• France Dr Jacques MARTINI (Toulouse, France)• Germany Pr Ralph LOBMANN (Stuttgart, Germany)• Italy Pr Alberto PIAGGESI (Pisa, Italy)• Spain Pr Jose-Luis LAZARO MARTINEZ (Madrid, Spain)• UK Pr Michael EDMONDS (London, UK)

Acknowledgments to :- Dr Jean-Louis RICHARD () (France) for his contribution in the conception of

the trial - Pr David ARMSTRONG (USA) and Pr Antonia PEREZ-MARTIN (France)

for their contribution regarding the vascular part of the Protocol

The EXPLORER RCT in Europe

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The EXPLORER RCT

Design Randomised, double-blind, controlled trial in two parallel groups

Objective To demonstrate that TLC-NOSF wound dressing is superior to the same dressing without TLC-NOSF, inthe local treatment of neuro-ischaemic DFU

Investigation center43 centres in France, Germany, Italy, Spain and the UK

Primary endpoint Complete wound closure* rate after 20 weeks of treatment with the studied wound dressings

Treatment arms 2 treatment arms with a total of 240 patients

Indication Neuro-ischaemic DFU

Duration20 weeks treatment with 12 weeks follow-up

Aetiological treatment Both arms were treated with standard of care, including off-loading

*Complete wound closure is defined as 100% reduction in DFU surface area with full epithelialization of the target DFU, without exudates and has to be confirmed 2 weeks later (Wx+2) by the investigator

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What is the Mode of Action of the Treatment evaluated in the EXPLORER study?

Beyond the underlying aetiology of Diabetic Foot Ulcers, two key local factors significantly impair wound healing from the beginning.

1. A prolonged inflammatory phase with increased levels of Matrix Metalloproteinases (MMPs)1, which are present from the beginning of the wound and destroy essential extracellular matrix (ECM) components

1. Lazaro JL, Izzo V, Meaume S, Davies AH, Lobman Rm Uccioli L. Elevated levels or matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence. J Wound Care 2016: 25(5):277-287. 2. Honnegowda TM, Kumar P, Udupa EG, Kumar S, Kumar U, Rao P. Role of angiogenesis and angiogenic factors in acute and chronic wound healing. Plast Aesthet Res 2015;2:243-9. Role of angiogenesis and

angiogenic factors in acute and chronic wound healing.

2. An impaired neovascularisation2 leading to defective granulation tissue formation

→ In addition to the aetiological treatment such as off-loading,local treatment is needed to act on these local impeding factors.

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What is the Mode of Action of the Treatment evaluated in the EXPLORER study?UrgoStart is composed of a unique TLC-NOSF Healing Matrix (NOSF* impregnated in a TLC healing matrix), which acts locally in the wound, on 2 key factors significantly impairing wound healing:

→ UrgoStart, in addition to aetiological treatment, acts on 2 key local factors impeding wound healing. Therefore more wounds can be closed and the time to healing is reduced.

1. Inhibition of excess Matrix Metalloproteinases (MMPs) 1: KSOS has been shown to inhibit MMPs1. Since MMPs are the main enzymes implicated in the extracellular matrix (ECM) degradation, their inhibition will result in a reduction of proteolytic destruction of essential ECM components2,3 .

2. Restoration of neovascularisation by reactivating vascular cells proliferation and migration 1,4: KSOS has a unique structure that interacts with growth factors, particularly those acting on vascular cells 1,4. Thus, it promotes proliferation and migration of vascular cells, restoring neovascularisation.

*NOSF (Nano OligoSaccharideFactor) = KSOS (potassium sucrose octasulfate)

1. White, R., Cowan, T., Glover, D. Supporting evidence-based practice: a clinical review of TLC healing matrix (2nd edition). MA Healthcare Ltd, London, 2015.2. Lazaro JL, Izzo V, Meaume S, Davies AH, Lobman Rm Uccioli L. Elevated levels or matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence. J Wound Care 2016: 25(5):277-287. 3. Coulomb B, Couty L, Fournier B, et al. A NOSF (Nano-Oligosaccharide Factor) lipido-colloid dressing inhibits MMPs in an in vitro dermal equivalent model. Wound Rep Regen 2008; 16-A64 (Meeting of the European Tissue Repair Society and Wound Healing Society)4. Edmonds M, Lázaro JL, Piaggesi A, et al. Sucrose octasulfate dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers (Explorer): an international, multicentre, double-blind, randomised, controlled trial. The Lancet Diabetes & Endocrinology. Published online December 20, 2017

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13

Randomised, double blind, controlled and stratified trial, conducted in 2 parallel groups

The EXPLORER RCT. Diagram

D-14 D0

Run-inperiod

• Patient consent• Validation of inclusion and

exclusion criteria• Prescription of an off- loading

system

M0

❶

❶ Run-in period

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14



+ NOSF

D-14 D0 W2 W4 W8 W12 W16 W20

- NOSFRun-inperiod

• Wound surface area D-14 vs W0 ≤ 30%• No infection (whatever wound, whatever limb)• Off- loading compliance confirmed• HbA1c ≤10% (if not available at D-14)



system

M0 M1 W6 M2 W1 0 M3 W14 M4 W1 M5

❶

❷

2

❶ Run-in period

Randomisation (D0) + Treatment period (D0 – W20)

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15



+ NOSF

D-14 D0 W2 W4 W W8 W10 W12 W1 W16 W1W20 W24 W28 W32

- NOSFRun-inperiod

Follow-up: Ancillary study

• Wound surface area D-14 vs W0 ≤ 30%• No infection (whatever wound, whatever limb)• Off- loading compliance confirmed• HbA1c ≤10% (if not available at D-14)



system

Urgostart® Contact

M0 M1 W6 M2 W1 0 M3 W14 M4 W1 M5 M6 M7 M8

All the patients will participate to the follow-up study.In case of wound closure, at any time of the follow-up, the

epithelialisation will be assessed two weeks after.

❶

❷

❸

Randomisation (D0) + Treatment period (D0 – W20)

2

❸

❶ Run-in period

Follow-up: Ancillary study

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▪ Neuro-ischaemic DFU with adequate arterial blood supply on the target limb, based on

Ankle Brachial Pressure Index (ABPI) and the level of Toe or Ankle pressure (STBP or

SABP) (mild to moderate ischaemia)

▪ DFU Grade I-C or II-C (University of Texas Diabetic Wound Classification*)

→ Grade I-C: ischemic, non-infected superficial ulceration

→ Grade II-C: ischemic, non-infected ulcer that penetrates to tendon or capsule

*Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care. 1998 May;21(5):855-59

The EXPLORER RCT – The DFU

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RESULTS

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60% moreDFUs healed by 20 weeks

were observed in the TLC-

NOSF group compared to an

advanced neutral dressing

Control TLC-NOSF

Percentage of Wound Closure by Week 20

34/114

30%60/126

48%∆ = 18ptsP = 0,002

+60%

0dds Ratio: 2.60(1.43 – 4.73)

on average, 2.6 higher odds to

healWound closure: Defined as 100% epithelialization with no drainage and confirmed two weeks later by the investigators.

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TLC-NOSF shortened the mean time to closure by

60 days

Control TLC-NOSF

Mean tome to closure (days)

-60 days180 d

120 d

Data are given as mean ± SE (95% CI). Median value are not given as the control group did not reach 50% of wound closure.Estimation is limited to the largest survival time if it is censored. Confirmed closure population.

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“THE SOONER, THE BETTER”

73% MoreWounds closure when wound duration is less than 2 months

<2 months 2 - 6 months >6 months

41%

71%

38%

59%

15%

25%

Control TLC-NOSF

+73%

+55%

+66%

Percentage of Wound Closure by Week 20

Wound closure: Defined as 100% epithelialization with no drainage and confirmed two weeks later by the investigators.

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CONCLUSION (Explorer study)

Treating neuro-ischaemic DFU with TLC-NOSF leads to:

✓A significant superiority on wound closure rate: 18 pts difference vs. control

✓60% more patients healed with TLC-NOSF treatment vs. a neutral dressing

✓the sooner the treatment is used, the greater the results

✓A significant reduction of time to closure: 60 days

✓Positive outcomes in all sub-groups (duration/surface/location of the wounds)

✓A highly favorable benefit/risk ratio

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HOW TO IMPLEMENT TLC-NOSF IN YOUR DAILY PRACTICE

«Sucrose octasulfate dressing could be considered as the

new standard of care» according to the Lancet position.

✓ Neuroischemic DFUs / All DFUs??

✓ First-line treatment until wound closure

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PATHWAY FOR DIABETIC FOOT ULCERATION

FPT: Foot Protection Team; MDFT: Multidisciplinary Foot Team

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THANK YOU FOR YOUR ATTENTION

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A breakthrough in the management of neuro- ischaemic