Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies

doi:10.1016/S0140-6736(09)60322-6

The Lancet

Volume 373, Issue 9671, 11–17 April 2009, Pages 1264-1274

https://doi.org/10.1016/S0140-6736(09)60322-6 Get rights and content

Summary

Background

Research into mechanisms of skin scarring identified transforming growth factor β3 (TGFβ3) as a potential antiscarring therapy. We assessed scar improvement with avotermin (recombinant, active, human TGFβ3).

Methods

In three double-blind, placebo-controlled studies, intradermal avotermin (concentrations ranging from 0·25 to 500 ng/100 μL per linear cm wound margin) was administered to both margins of 1 cm, full-thickness skin incisions, before wounding and 24 h later, in healthy men and women. Treatments (avotermin and placebo or standard wound care) were randomly allocated to wound sites by a computer generated randomisation scheme, and within-participant controls compared avotermin versus placebo or standard wound care alone. Primary endpoints were visual assessment of scar formation at 6 months and 12 months after wounding in two studies, and from week 6 to month 7 after wounding in the third. Investigators, participants, and scar assessors were blinded to treatment. Efficacy analyses were intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00847925, NCT00847795, and NCT00629811.

Results

In two studies, avotermin 50 ng/100 μL per linear cm significantly improved median score on a 100 mm visual analogue scale (VAS) by 5 mm (range −2 to 14; p=0·001) at month 6 and 8 mm (−29 to 18; p=0·0230) at month 12. In the third, avotermin significantly improved total scar scores at all concentrations versus placebo (mean improvement: from 14·84 mm [95 % CI 5·5–24·2] at 5 ng/100 μL per linear cm to 64·25 mm [49·4–79·1] at 500 ng/100 μL per linear cm). Nine [60%] scars treated with avotermin 50 ng/100 μL per linear cm showed 25% or less abnormal orientation of collagen fibres in the reticular dermis versus five [33%] placebo scars. After only 6 weeks from wounding, avotermin 500 ng/100 μL per linear cm improved VAS score by 16·12 mm (95% CI 10·61–21·63). Adverse events at wound sites were similar for avotermin and controls. Erythema and oedema were more frequent with avotermin than with placebo, but were transient and deemed to be consistent with normal wound healing.

Interpretation

Avotermin has potential to provide an accelerated and permanent improvement in scarring.

Funding

Renovo (UK).

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

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ArticlesProphylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies

Summary

Background

Methods

Results

Interpretation

Funding

Introduction

Section snippets

Study design and population

Results

Discussion

J Invest Dermatol

Br J Plast Surg

Dev Biol

Int J Biochem Cell Biol

Lancet

Genetic susceptibility to keloid disease: transforming growth factor beta receptor gene polymorphisms are not associated with keloid disease

Exp Dermatol

Emerging new drugs for scar reduction

Expert Opin Emerg Drugs

International clinical recommendations on scar management

Plast Reconstr Surg

Articles
Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies