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Trial registered on ANZCTR


Registration number
ACTRN12610000760077
Ethics application status
Approved
Date submitted
24/08/2010
Date registered
14/09/2010
Date last updated
14/09/2010
Type of registration
Retrospectively registered

Titles & IDs
Public title
Investigation of cell therapy for recessive dystrophic epidermolysis bullosa (RDEB) in Australia through intradermal injection of allogeneic fibroblasts.
Scientific title
In adult patients with recessive dystrophic epidermolysis bullosa (RDEB), are intradermal allogeneic cultured fibroblast wound injections in transport solution (Plasmalyte and 2% albumex) more effective than a placebo in promoting wound healing and collagen production?
Secondary ID [1] 251952 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Recessive dystrophic epidermolysis bullosa 257638 0
Condition category
Condition code
Skin 257816 257816 0 0
Dermatological conditions
Human Genetics and Inherited Disorders 258313 258313 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will have paired ulcers randomly treated with intradermal injection of cultured allogeneic fibroblasts (5 x10^6 per cm2) in a plasmalyte and 2% albumex solution. This will be performed during the baseline visit.

Each paired ulcer site (placebo and treatment) will be treated with plasmalyte and 2% albumex solution injections or fibroblasts in a plasmalyte and 2% albumex solution. These paired sites will be injected at the same time or shortly after one another during the baseline visit.

At 6 months, if the patient chooses to have the treatment sites re-treated with fibroblast injections, then the opportunity will be provided for patients to have this performed.
Intervention code [1] 256714 0
Treatment: Other
Comparator / control treatment
Intradermal injection the base solution without the fibroblasts, consisting of Plasmalyte solution with 2% albumex. These ulcers will be injected during the baseline visit.
Control group
Placebo

Outcomes
Primary outcome [1] 258675 0
Primary outcome will be difference in area of the wound size from baseline to predetermined time points of the fibroblast injected wounds vs the placebo injected wounds. This will be achieved using the Visitrak wound measurement system [Smith & Nephew Healthcare Ltd., Hull]. Wounds will be serially measured for ulcer size and healing will be determined based on reduction in ulcer size from baseline measurements.
Timepoint [1] 258675 0
Over a 12 month period, patients are monitored at:
Baseline, Weeks 2,4,8,12,24,48.
Primary outcome [2] 258676 0
To investigate the effect of cell therapy with cultured allogeneic fibroblasts on increasing the production of collagen VII in skin and restoration of normal skin electron microscopy ultrastructure (i.e. anchoring fibrils). Change in Col VII expression levels between base of ulcer at baseline and predetermined time points between the fibroblast injected ulcers and placebo injected ulcers. Collagen VII levels will determined via skin biopsies and direct immunofluorescence testing for collagen VII using LH7.2 and FNC1 antibodies to collagen VII. Anchoring fibril development will be determined via electron microscopy.
Timepoint [2] 258676 0
Over a 12 month period, patients are monitored at:
Baseline, Weeks 2,4,8,12,24,48.
Secondary outcome [1] 264678 0
Percent change in size of wounds for each treatment group.
This will be achieved using the Visitrak wound measurement system [Smith & Nephew Healthcare Ltd., Hull]. Wounds will be serially measured for ulcer size and healing will be determined based on reduction in ulcer size from baseline measurements. Percentage reduction will be mathematically calculated uby comparing ulcer sizes at each time point with baseline values.
Timepoint [1] 264678 0
Over a 12 month period, patients are monitored at:
Baseline, Weeks 2,4,8,12,24,48.
Secondary outcome [2] 264679 0
Change in appearance score of wounds for each treatment group as assessed by investigator and patient. The tool used for this will be the Visual Analogue Scale which provides a score from 1-10 and the numbers will be evaluated over the time points from the subjects' and the investigator's perspective.
Timepoint [2] 264679 0
Over a 12 month period, patients are monitored at:
Baseline, Weeks 2,4,8,12,24,48.
Secondary outcome [3] 264680 0
Change in pain score of wounds for each treatment group.
Timepoint [3] 264680 0
Over a 12 month period, patients are monitored at:
Baseline, Weeks 2,4,8,12,24,48.
Secondary outcome [4] 264681 0
Change in pruritus score (VAS) of wounds for each treatment group. The tool used for this will be the Visual Analogue Scale which provides a pain score from 1-10 and the numbers will be evaluated over the time points.
Timepoint [4] 264681 0
Over a 12 month period, patients are monitored at:
Baseline, Weeks 2,4,8,12,24,48.
Secondary outcome [5] 265171 0
Change in Quality of Life score per patient over the time points. The tool used for this will be the Quality of Life in Epidermolysis Bullosa (QOLEB), an objective and disease specific measurement tool for measuring quality of life in patients with epidermolysis bullosa
Timepoint [5] 265171 0
Over a 12 month period, patients are monitored at:
Baseline, Weeks 2,4,8,12,24,48.

Eligibility
Key inclusion criteria
1. Diagnosis of Recessive dystrophic epidermolysis bullosa- generalized severe (RDEB-GS) (patients should have detectable low levels of collagen VII expression and reduced / abnormal anchoring fibrils on electron microscopy).
2. At least 2 symmetric wounds on each side of the body (arms, chest/abdomen, legs) of approximately the same size (at least 4 cm2 as measured accurately by the Visitrak wound measurement system [Smith & Nephew Healthcare Ltd., Hull]).
3. Ability to sign informed consent, which indicates the investigational nature of this study.
4. Age: 18 years or older
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Clinical evidence of local infection of the targeted wound(s).
2. Histopathologic evidence of malignancy (i.e. squamous cell carcinoma - SCC) of the targeted wound(s).
3. Use of systemic or topical steroid therapy within 30 days before enrolment.
4. Use of any investigational drug within the 30 days before enrolment.
5. Patients considered by the investigators to be unreliable or have poor compliance
6. Patients who are pregnant, or who suspect they may be pregnant at the time of the study and lactating women. Women of childbearing age should use effective contraception.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients with a diagnosis of RDEB-GS seen at St George Hospital (Kogarah) will be recruited for the study. This study will be offered to patients who fulfil the inclusion criteria regardless of gender, race or ethnicity. Clinical investigators will discuss with the patient his/her diagnosis, risks and benefits of study participation, as well as treatment alternatives. All approached patients will be documented and consented by an investigator prior to enrolment on the study. Patients will be reassured that participation in the trial is voluntary, and that their decision would in no way influence their ongoing care. Patients have a screening biopsy of their inner arm which must have reduced but detectable collagen VII expression and no history of squamous cell carcinoma.
For each enrolled patient, two to eight symmetric wounds on each side of the body (arms, chest/abdomen, legs) of approximately the same size and duration (at least 4 cm2 as measured accurately by the Visitrak wound measurement system [Smith & Nephew Healthcare Ltd., Hull], will be identified by a study dermatologist. Patients will then be scheduled for study treatment within a week.

Each paired site will be treated with either fibroblast or placebo solution. It was determined ahead of time on test shipments that the cloudy nature of the fibroblast solution could best be concealed from the clinical investigators and patients by covering the syringes with several layers of parafilm. The sterile 2ml with 0.25ml gradations luer-lock syringes were pre-labelled A or B, covered with parafilm and given to the research pharmacist. The randomization code was generated according to a computer generated randomization list and ensured that A and B syringes did not remain for the same treatment for consecutive patients. The master randomization list was kept in an opaque sealed envelope at the Pharmacy, St George Hospital (Kogarah) until the completion of the study. The pharmacist drew up the active and placebo solutions into the pre-labelled syringes (A and B) and these were delivered to the procedure room for injection along with a sheet showing which site numbers these were to be injected into.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization code was a computer generated program which alternated A and B for each wound for up to 8 paired wounds per patient.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This is a randomized, single-institution double-blind, placebo-controlled clinical trial. The unit of randomisation is the wound. Each paired site in patients is randomly chosen to receive either placebo or fibroblast injections.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 3151 0
2121
Recruitment postcode(s) [2] 3150 0
2400
Recruitment postcode(s) [3] 3152 0
3796
Recruitment postcode(s) [4] 3255 0
5211
Recruitment outside Australia
Country [1] 2684 0
New Zealand
State/province [1] 2684 0
Waipu, Northland

Funding & Sponsors
Funding source category [1] 257454 0
University
Name [1] 257454 0
University of New South Wales (UNSW) Australian Postgraduate Awards
Address [1] 257454 0
Faculty of Medicine
UNSW
High St
Kensington
NSW 2033
Country [1] 257454 0
Australia
Funding source category [2] 257455 0
Charities/Societies/Foundations
Name [2] 257455 0
America Australia Association
Address [2] 257455 0
50 Broadway, Suite 2003
New York, NY 10004
Country [2] 257455 0
United States of America
Funding source category [3] 257643 0
Self funded/Unfunded
Name [3] 257643 0
Premier Dermatology Trials (Part of Professor Dedee Murrell's private pratice)
Address [3] 257643 0
17 Kensington St
Kogarah, Sydney
NSW, Australia
2217
Country [3] 257643 0
Australia
Primary sponsor type
Government body
Name
Research Infrastructure Support Services (RISS)
Address
GPO Box 5103
Melbourne,
Victoria 3001
Country
Australia
Secondary sponsor category [1] 256440 0
Charities/Societies/Foundations
Name [1] 256440 0
Women's Dermatologic Society
Address [1] 256440 0
700 N Fairfax St. Suite 510
Alexandria, VA 22314
Country [1] 256440 0
United States of America
Secondary sponsor category [2] 256684 0
Charities/Societies/Foundations
Name [2] 256684 0
DebRA Australia
Address [2] 256684 0
P O Box 226
Pittsworth
QLD 4356
Country [2] 256684 0
Australia
Secondary sponsor category [3] 256685 0
Charities/Societies/Foundations
Name [3] 256685 0
DebRA New Zealand
Address [3] 256685 0
123 Daniell Street, Newtown, Wellington
New Zealand 6021
Country [3] 256685 0
New Zealand
Other collaborator category [1] 251336 0
Individual
Name [1] 251336 0
Professor Dedee F Murrell (Principal Investigator)
Address [1] 251336 0
Department of Dermatology,
St George Hospital, Gray St, Kogarah, Sydney, NSW 2217
UNSW Faculty of Medicine, Sydney, NSW 2033
Country [1] 251336 0
Australia
Other collaborator category [2] 251337 0
Individual
Name [2] 251337 0
Professor Ishida-Yamamoto
Address [2] 251337 0
Department of Dermatology,
Asahikawa Medical College,
Midorigaoka Higashi 2-1-1-1
Asahikawa, 078-8510
Country [2] 251337 0
Japan
Other collaborator category [3] 251338 0
Individual
Name [3] 251338 0
Professor P. Marinkovich
Address [3] 251338 0
Center for Clinical Sciences Research (CCSR)
Building Rm 2145
Stanford CA 94305
Country [3] 251338 0
United States of America
Other collaborator category [4] 251339 0
Individual
Name [4] 251339 0
Mrs. J. Fogarty
Address [4] 251339 0
Cell & Tissue Therapies WA (CTTWA)
Royal Perth Hospital
Wellington Street
Perth 6000
Western Australia
Country [4] 251339 0
Australia
Other collaborator category [5] 251340 0
Individual
Name [5] 251340 0
Dr Marian Sturm
Address [5] 251340 0
Cell & Tissue Therapies WA (CTTWA)
Royal Perth Hospital
Wellington Street
Perth 6000
Western Australia
Country [5] 251340 0
Australia
Other collaborator category [6] 251341 0
Individual
Name [6] 251341 0
Mrs. Janis Nelson
Address [6] 251341 0
Dept of Pharmacy
St George Hospital
Kogarah, Sydney
NSW 2217
Country [6] 251341 0
Australia
Other collaborator category [7] 251342 0
Individual
Name [7] 251342 0
Dr. Wei Melbourne
Address [7] 251342 0
Dept of Anatomical Pathology,South Eastern Area Laboratory Services (SEALS),
St George Hospital
Kogarah, Sydney
NSW 2217
Country [7] 251342 0
Australia
Other collaborator category [8] 251343 0
Individual
Name [8] 251343 0
Dr. Kim Tran
Address [8] 251343 0
Dept of Anatomical Pathology, South Eastern Area Laboratory Services (SEALS)
St George Hospital
Kogarah, Sydney
NSW 2217
&
University of New South Wales (UNSW)
Faculty of Medicine
High St
Kensington
NSW 2033
Country [8] 251343 0
Australia
Other collaborator category [9] 251432 0
Individual
Name [9] 251432 0
Dr Wenfei (Hellen) Yan
Address [9] 251432 0
Dept of Dermatology
St George Hospital
Kogarah, Sydney
NSW 2217
&
UNSW Faculty of Medicine PhD program
UNSW
Faculty of Medicine
High St
Kensington
NSW 2033
Country [9] 251432 0
Australia
Other collaborator category [10] 251433 0
Individual
Name [10] 251433 0
Dr John Frew
Address [10] 251433 0
Dept of Dermatology
St George Hospital
Kogarah, Sydney
NSW 2217
Country [10] 251433 0
Australia
Other collaborator category [11] 251434 0
Individual
Name [11] 251434 0
Mrs Lesley Rhodes
Address [11] 251434 0
Dept of Dermatology
St George Hospital
Kogarah, Sydney
NSW 2217
Country [11] 251434 0
Australia
Other collaborator category [12] 251435 0
Individual
Name [12] 251435 0
Dr Heather I Cohn
Address [12] 251435 0
Dept of Dermatology
St George Hospital
Kogarah, Sydney
NSW 2217
Country [12] 251435 0
Australia
Other collaborator category [13] 251436 0
Individual
Name [13] 251436 0
Dr Supriya Venugopal
Address [13] 251436 0
Dept of Dermatology
St George Hospital
Kogarah, Sydney
NSW 2217
&
UNSW Faculty of Medicine PhD program
UNSW
Faculty of Medicine
High St
Kensington
NSW 2033
Country [13] 251436 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259476 0
South Eastern Sydney and Illawarra Area Health Service
Ethics committee address [1] 259476 0
Level 3,
James Laws Building
St George Hospital
Kogarah, Sydney
NSW 2217
Ethics committee country [1] 259476 0
Australia
Date submitted for ethics approval [1] 259476 0
27/03/2007
Approval date [1] 259476 0
04/05/2007
Ethics approval number [1] 259476 0
HREC 07/28

Summary
Brief summary
This is a randomized, single-institution double-blind, placebo-controlled clinical trial. Enrolled patients with a diagnosis of RDEB-GS will be randomized to receive either cell therapy with intradermal injection of cultured allogeneic fibroblasts in transport media or placebo (i.e. transport media alone) on two to eight symmetrical wounds on each side of their body (arms, trunk, upper and lower legs).

Up to 5 patients will be enrolled. All patients will undergo clinical examination, photography and skin punch biopsies for immunofluorescence and electron microscopy studies (if not previously done). The efficacy endpoint for the primary objective is median healing time of lesions for each treatment group (fibroblast-treated versus placebo). Secondary efficacy end points are percentage change in size, change in appearance score (VAS), pain score (VAS) and pruritus score (VAS) of wounds for each treatment group.
The efficacy endpoint for the co-primary objective are quantitative change in expression of collagen VII on immunofluorescence mapping and change in electron microscopy ultrastructure (i.e. numbers and appearance of anchoring fibrils) after cell therapy.
Trial website
Trial related presentations / publications
European Society for Dermatological Research, Budapest, Sept 2009 (oral paper), EB 2009 Vienna; St George Hospital Annual Symposium - winner of best clinical research award, 2009; American Academy of Dermatology - residents and Fellows section, Miami 2010 (oral); Australian Wound and Tissue Therapies Conference, Perth, WA (oral, by invitation); Australasian College of Dermatologists Annual Meeting, Darwin - oral presentation; Australasian Society for Dermatological Research, Cairns, QLD (oral); European Soc Derm Res, Helsinki, Finland - Plenary presentation; Australian Dermatopathology Society Annual Meeting 2010, (shortlisted for Brenan prize division).
Public notes

Contacts
Principal investigator
Name 31263 0
Address 31263 0
Country 31263 0
Phone 31263 0
Fax 31263 0
Email 31263 0
Contact person for public queries
Name 14510 0
Professor Dedee F Murrell
Address 14510 0
Dept of Dermatology
Ground Floor
James Laws House
St George Hospital
Kogarah, Sydney
NSW 2217
Country 14510 0
Australia
Phone 14510 0
+61 2 91132543
Fax 14510 0
+61 2 91132906
Email 14510 0
d.murrell@unsw.edu.au
Contact person for scientific queries
Name 5438 0
Professor Dedee F Murrell
Address 5438 0
Dept of Dermatology
Ground Floor
James Laws House
St George Hospital
Kogarah, Sydney
NSW 2217
Country 5438 0
Australia
Phone 5438 0
61 2 91132543
Fax 5438 0
61 2 91132906
Email 5438 0
d.murrell@unsw.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary