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Trial registered on ANZCTR

Registration number

ACTRN12618002003257

Ethics application status

Approved

Date submitted

6/12/2018

Date registered

13/12/2018

Date last updated

13/12/2018

Date data sharing statement initially provided

13/12/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Full-thickness cultured skin to heal significant burns without needing skin grafts

Scientific title

A prospective evaluation of Cultured Composite Skin (CCS) as a definitive closure second stage [where biodegradable polyurethane dermal matrix (BTM) represents the first stage] in the management of extensive deep burn injury.

Secondary ID [1]

CCS/01/2016 (Sponsor study reference number)

Universal Trial Number (UTN)

U1111-1225-1616

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Significant burns (Full-thickness burn injuries between 30% and 100% Total Body Surface Area)

Condition category

Condition code

Injuries and Accidents

Burns

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

A prospective, 5 patient, non-controlled, non-blinded, single-arm pilot efficacy trial involving participants ranging from those with life-threatening burn injuries, up to and including those meeting the criteria for non-survivable burn injury (where this treatment offers the only chance of survival). All treatments will be administered during the participant's inpatient admission to the Royal Adelaide Hospital. At the first operation in the operating theatre, under general anaesthesia, the participant will have ALL deep burn excised.The operative area will be aggressively scrubbed with betadine-impregnated brushes, wet and dry Raytek gauze packs to clean the burns, remove all surface contaminants, loose non-viable material, etc. and shaved of hair. Skin preparation will be with Betadine™ (povidone iodine solution), unless the subject has a demonstrated history of iodine sensitivity/allergy when alcoholic chlorhexidine solution will be used. After draping, and under aseptic conditions, the deep areas of burn will be outlined for excision using a Sommerlad pen and Bonney’s Blue ink. The deep burn will be tumesced subcutaneously with a solution of 1:500,000 adrenaline and 0.05% bupivacaine to reduce intraoperative blood loss and post-operative pain. The burn will then be excised with a Watson-Humby knife to viable tissue. Haemostasis will be secured by bipolar diathermy and adrenaline-soaked packs (1:10,000). A biopsy (split skin graft) 10cm x 20cm harvested from unburned skin to create the autologous Composite Cultured Skin (CCS). This will be grown over the next 5 weeks. After this debridement, the wounds will be 'passively' temporised with an epidermal skin substitute (Biobrane). This will be overdressed with Acticoat, held by crepe bandages (limbs) or adhesive tapes (trunk).

At a second operation (two or three days after the first operation also under general anaesthesia in theatre), the Biobrane will be removed, the wounds refreshed and BTM will be applied to all deep areas, except face, soles of feet and palms of hands. feet and hands. The BTM will be held in place with surgical steel staples. Overdressing will be with Acticoat™ nanocrystalline silver dressing held with hypafix on the trunk and crepe bandages on the limbs. Once recovered from anaesthesia, the patient will be returned to the ward, or Intensive Care Unit as required. The dressings will be taken down every three days for inspection. Evidence of material integration (colour, loss of foam pattern, general appearance) will be sought and recorded. Digital photographs will be taken. Staples will be removed at BTM delamination and CCS application. Dressing changes will occur on the ward every three days until the BTM is integrated and the CCS is ready for transplantation (about 5 weeks after the first operation) and the third operation is performed where the seal of the BTM is removed and the CCSs are applied, fixed and dressed under general anaesthetic. Dressings are again every three days until healing. The surgeries will all be performed by a specialist plastic surgery-trained burns surgeon with at least 10 years specialist burn surgery experience, with junior staff and theatre nurses. The intervention should need only one application, although in larger cases, some additional touch-up applications may be required. With burn injuries of this severity, early surgery is performed under two doctor, or third party consent. However, the participant is expected to be awake, cognisant and responsible by the time the CCS is ready for transplantation. At that stage, involvement in the trial will be discussed and information sheets provided to participant, next of kin and other family regarding the trial treatment, before informed consent is obtained, or involvement in the trial is refused.

Intervention code [1]

Treatment: Devices

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

CCS ‘take’ (this will be assessed clinically and by punch biopsy once epithelialisation becomes apparent – in pig trials this occurred between Day 7-10)

Timepoint [1]

28 days post-CCS application (approximately 9 weeks post-injury)

Primary outcome [2]

Ratio of CCS take:loss (if there is partial loss/failure of CCS, this ratio can be calculated, knowing the size (area) of the CCS pieces (each piece is 25 x 25cm).

Timepoint [2]

28 days post-CCS application (approximately 9 weeks post-injury)

Secondary outcome [1]

Scar quality after healing of the split skin graft (demonstrated by Matching Assessment using Photographs with Scars - MAPS). Baseline to be taken post-BTM integration, pre-CCS application; final measurement at 12 months post-CCS application.

Timepoint [1]

12 months post-CCS application

Secondary outcome [2]

Therapist and patient satisfaction with outcome (demonstrated by a therapist delivered, patient orientated outcome scale - the Patient and Observer Scar Assessment Scale v.2 (POSAS)). Baseline to be taken post-BTM integration, pre-CCS application; final measurement at 12 months post-CCS application.

Timepoint [2]

12 months post-CCS application

Eligibility

Key inclusion criteria

• Patients with deep (deep dermal or full thickness burns), between 30% and 100% (inclusive) of their total body surface area (TBSA) requiring split skin grafting.

Minimum age

18 Years

Maximum age

70 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

• Pregnancy/Lactation
• Non-English speakers (from an informed consent perspective), unless an information and consent form in the subject’s language is available along with a study coordinator capable of answering questions in that language.
• Known allergy/previous reaction to polyurethane dressing materials
• Unwillingness to consent, or unwillingness of next of kin (NOK) or immediate family to provide consent.

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Not applicable

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Not applicable

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Data will be collected up to 12 months post-injury. Participant/carers will be advised to massage and moisturize the healed burn areas with aqueous moisturizing creams at least three times a day in the early follow-up and reducing to once a day by 1 year post-graft application. Scar modulation with compression garments will be provided and continued until maturation is advanced. Physiotherapy and occupational therapy will commence early and be aggressive, providing additional scar modulation with silicone sheeting where necessary. Therapy assessment of MAPS, joint ROM and POSAS should be made at 3, 6 and 12 months, although only the 12 month record forms a secondary outcome measure. Digital photography of progress, with video where results are deemed interesting or important, will be taken at each of these therapy reviews. Therapy/medical review is likely to be more frequent - if a feature of healing or outcome is felt to be important, or interesting, it should also be recorded photographically.

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

The small pilot sample size and proof-of-concept nature of the trial, preclude in-depth statistical analysis.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

1/01/2019

Actual

Date of last participant enrolment

Anticipated

31/12/2019

Actual

Date of last data collection

Anticipated

31/12/2020

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

The Royal Adelaide Hospital - Adelaide

Recruitment postcode(s) [1]

5000 - Adelaide

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

The Lifetime Support Authority

Address [1]

30, Wakefield Street, Adelaide 5000, South Australia

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Skin Tissue Engineering Pty Ltd

Address

PO Box 469, Unley, SA 5061

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

Hospital

Name [1]

Royal Adelaide Hospital

Address [1]

1, Port Road, Adelaide 5000, South Australia

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Adelaide Local Health Network HREC

Ethics committee address [1]

CALHN (Central Adelaide Local Health Network) Research Office, Level 3, Roma Mitchell House, North Terrace, Adelaide 5000, South Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

15/05/2018

Approval date [1]

24/07/2018

Ethics approval number [1]

HREC/18/CALNH/322

Summary

Brief summary

In patients with large burns, skin grafts are sometimes not available. Even when they are available, they involve the creation of new wounds and provide wound repair that is not like the skin that has been lost. Fourteen years of work at the Royal Adelaide Hospital have permitted the production of two products (BTM and CCS). BTM is applied to the wounds after the burn has been removed and integrates into the wound. At the same time the CCS is being grown in the laboratory from a small sample of the patient's skin. This takes 5 weeks. When ready, the CCS is applied over the BTM and the wound is healed WITHOUT the need for skin grafts.

Trial website

Trial related presentations / publications

Public notes

In deep burns, burned tissue begins to ‘break down’ into toxins if left on the body and it is vital that the deep burn is removed as soon as possible after injury. This means that large wounds are created. To close these wounds, we usually harvest skin grafts from large areas of unburned skin, ‘mesh’ it to make it able to cover more burn area and apply it to the wounds left after burn removal. As burn size increases, so donor site increases. Grafts on bigger burns are often ‘meshed’ wider, because there is less donor site available. The bigger the mesh, the less functional and attractive the result. In very big burns (more than half the body burned), there is not much donor site at all and we have to use different methods to heal the wounds.

We are investigating a way to replace the need for skin grafts. This needs two materials; a new skin substitute called BTM (or Biodegradable Temporising Matrix), made from a plastic (polymer) and designed to protect the wound and to become the initial part of the skin repair and a full-thickness cultured skin material called CCS which is grown from your own skin cells and takes 4 – 5 weeks to make. We’ve already demonstrated that BTM works and we use this now at the Royal Adelaide Hospital for major burn management. 

This study will assess the second material, CCS. Once the BTM material has integrated and the CCS is ready (prepared from a small skin graft from an unburned area), four to five weeks later, the outer part of the first material is removed and the CCS will be applied to the surface of the BTM material to close the wounds. 

Several publications document the CCS development and are listed here:

Book Chapters
JE Greenwood, MJD Wagstaff. ‘The use of biodegradable polyurethane in the development of dermal scaffolds’ Chapter 22 In Cooper SL & Guan J (Eds) ‘Advances in Polyurethane Biomaterials’ 2016. Woodhead Publishing Series in Biomaterials,  (Elsevier Inc.), Duxford, UK. ISBN:978-0-08-100614-6. 

JE Greenwood. ‘Hybrid biomaterials for skin tissue engineering’ Chapter 9 In Albanna MZ & Holmes JH IV (Eds) ‘Skin Tissue Engineering and Regenerative Medicine’ 2016. Academic Press (Elsevier Inc.), London, UK. ISBN:978-0-12-801654-1. 

Papers
A Li, BL Dearman, KE Crompton, TG Moore, JE Greenwood. ‘Evaluation of a novel biodegradable polymer for the generation of a dermal matrix’ Journal of Burn Care and Research 2009;30(4):717-728.

JE Greenwood, A Li, B Dearman, TG Moore. 'Evaluation of NovoSorb™ novel biodegradable polymer for the generation of a dermal matrix. Part 1: In-vitro studies' Wound Practice and Research 2010;18(1):14-22.

JE Greenwood, A Li, B Dearman, TG Moore. 'Evaluation of NovoSorb™ novel biodegradable polymer for the generation of a dermal matrix. Part 2: In-vivo studies' Wound Practice and Research 2010;18(1):24-34.

BL Dearman, K Stefani, A Li, JE Greenwood. ‘Take’ Of A Polymer-Based Autologous Cultured Composite ‘Skin’ On An Integrated Temporising Dermal Matrix: Proof Of Concept’ Journal of Burn Care and Research 2013;34(1):151-160. 

BL Dearman, A Li, JE Greenwood. ‘Optimisation of a Polyurethane Dermal Matrix and Experience with a Polymer-based Cultured Composite Skin’ Journal of Burn Care and Research 2014;35(5):437-448.

JE Greenwood. ‘The Evolution of Acute Burn Care - Retiring the Split Skin Graft’ Annals of the Royal College of Surgeons of England 2017;99:432-438. doi 10.1308/rcsann.2017.0110.
 
Published Abstracts
JE Greenwood, IM Griffiths, T Moore, K Crompton, T Gunatillake, R Adhikari
‘Design and synthesis of biodegradable polymers to create dermal regeneration scaffolds’
ANZ Journal of Surgery May 2008:78 (supplement):A11 (BA20).

JE Greenwood, A Li, B Dearman, IM Griffiths 
‘Biodegradable polymers – (i) in-vitro evaluation as dermal matrices’
ANZ Journal of Surgery May 2008:78 (supplement):A12 (BA22).

JE Greenwood, A Li, B Dearman, IM Griffiths
‘Biodegradable polymers – (ii) in-vivo evaluation as dermal matrices’
ANZ Journal of Surgery May 2008:78 (supplement):A12 (BA23).

JE Greenwood
‘Biodegradable polyurethane as a dermal matrix’
Journal of Burn Care and Research 2011;32(2) Suppl:S58.

JE Greenwood, B Dearman
‘Biodegradable polyurethane as a dermal matrix allowing immediate or delayed grafting’
ANZJS 2011;81 (Suppl. 1):A3.

JE Greenwood, BL Dearman
‘Wound closure over integrated polymer neo-dermes using cultured epithelial autograft and composite cultured ‘skin equivalents’
Journal of Burn Care and Research 2012;33(2) Suppl:S173.

JE Greenwood, BL Dearman, A Li ‘Experience with a polymer-based Cultured Composite Skin (CCS)’ Journal of Burn Care and Research 2013;34(2) (Supplement):S70.

Contacts

Principal investigator

Name

Prof John E Greenwood AM

Address

Director, Adult Burn Service, Royal Adelaide Hospital, Port Road, Adelaide 5000, South Australia, AUSTRALIA,

Country

Australia

Phone

+61 487 234243

Fax

[email protected]

Contact person for public queries

Name

John E Greenwood AM

Address

Director, Adult Burn Service, Royal Adelaide Hospital, Port Road, Adelaide 5000, South Australia, AUSTRALIA.

Country

Australia

Phone

+61 487 234243

Fax

[email protected]

Contact person for scientific queries

Name

John E Greenwood AM

Address

Director, Adult Burn Service, Royal Adelaide Hospital, Port Road, Adelaide 5000, South Australia, AUSTRALIA,

Country

Australia

Phone

+61 487 234243

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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