ArticlesProphylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies
Introduction
Skin is the most frequently injured tissue, and millions of people worldwide acquire scars every year. Clinical experience shows that patients want less noticeable scars, with colour and texture that closely resemble their normal skin.1 Some therapies aim to improve existing scars; however, these treatments are empirically based and do not have evidence of efficacy from randomised controlled trials.1, 2, 3 20 years of research into mechanisms of skin scarring identified transforming-growth factor β3 (TGFβ3)—a skin morphogenic factor synthesised predominantly by keratinocytes and fibroblasts—as a potential antiscarring therapy.4 Studies in rats showed improvements in scarring when TGFβ3 was injected intradermally into full-thickness skin wounds at surgery.5 Early induction of specific signalling and cellular cascades led to improved architecture of the healing dermis of cutaneous wounds and a substantial permanent improvement or absence of scarring.4
A clinical programme is assessing scar improvement with avotermin (Juvista; Renovo, Manchester, UK): recombinant, active, human TGFβ3. A phase I trial confirmed that intradermal avotermin (50–10 000 ng per 3-mm punch-biopsy wound) is well tolerated, and showed no evidence of impaired healing or enhanced systemic exposure to TGFβ3 at 2–4 h after dosing (clinical study RN1001-319-1001, data on file [available to readers on request]; Renovo). The maximum tolerated dose was not reached, and the highest dose assessed was much greater than TGFβ3 concentrations that improved scarring in rodents.5
We report results of a series of three double-blind, randomised controlled phase I/II proof-of-concept and dose-finding clinical trials that aimed to assess the effect of prophylactic administration of avotermin on skin scarring.
Section snippets
Study design and population
All studies were undertaken in Renovo's Clinical Trial Unit. Study 1002 completed in September, 2003; study 1005 in June, 2003; and study 0036 in August, 2007. Selection of the most appropriate study populations was a major consideration in design of these studies. We concluded, and the regulatory authorities and ethics committees concurred, that the studies should be undertaken in healthy volunteers rather than in patients. This decision was made to avoid the risk of any complications that
Results
In study 1002, 103 men were recruited and sequentially assigned to one of nine dose groups (webappendix p 1). Note that dose groups H and I in study 1002 were repeat-dose groups that were not included in the primary analysis of efficacy (only data from the primary analysis are presented here). 99 (96%) participants were white. Across the dose groups, mean age ranged from 24 years to 36 years and mean BMI from 24 to 27 kg/m2. Other baseline characteristics were balanced across the dose groups
Discussion
Our series of three randomised, within-participant controlled clinical trials have shown that intradermal administration of avotermin to incisions reduces subsequent skin scarring compared with control treatment. Studies 1002 and 1005 were exploratory and not sufficiently powered to establish a definitive dose-response curve. The study populations were predominantly male, because of inclusion and exclusion criteria designed to avoid inclusion of women of childbearing potential into these
References (17)
- et al.
Aging is associated with reduced deposition of specific extracellular matrix components, an upregulation of angiogenesis, and an altered inflammatory response in a murine incisional wound healing model
J Invest Dermatol
(1997) - et al.
The stretched scar: a clinical and histological study
Br J Plast Surg
(1978) - et al.
Immunohistochemical localization of growth factors in fetal wound healing
Dev Biol
(1991) - et al.
Transforming growth factor betas and wound healing
Int J Biochem Cell Biol
(1997) - et al.
Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta
Lancet
(1992) - et al.
Genetic susceptibility to keloid disease: transforming growth factor beta receptor gene polymorphisms are not associated with keloid disease
Exp Dermatol
(2004) - et al.
Emerging new drugs for scar reduction
Expert Opin Emerg Drugs
(2006) - et al.
International clinical recommendations on scar management
Plast Reconstr Surg
(2002)
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