Skin Fibrosis Clinical Trial
Official title:
Phase II, Multicenter, Randomized, Double-blind, Intraindividually Placebo Controlled Clinical Trial, to Evaluate Efficacy and Safety of p144 Topical Administration for Skin Fibrosis in Patients With Systemic Sclerosis
Transforming growth factor-beta 1 (TGF-β1) is consistently over expressed in most fibrotic diseases and displays a variety of profibrotic effects in fibroblasts. Activation of TGF-β receptors induces the activation of several kinase signalling cascades leading to the phosphorylation of SMAD proteins as well as to the activation of SMAD-independent kinases that collectively activate ECM synthesis and fibroblast growth and differentiation into myofibroblasts. TGF-β1 is one of the main mediators in the fibrotic process, associated to both scarring and a long list of pathologies related to chronic inflammation and which affect all type of organs and tissues. An increase in TGF-β1 mRNA and protein levels has been described in these processes. Peptide 144 (P144) is the acetic salt of a 14mer peptide from human TGF-β1 type III receptor (betaglycan). P144 TGF-β1-inhibitor has been specifically designed to block the interaction between TGF-β1 and TGF-β1 type III receptor, thus blocking its biological effects. P144 has shown significant antifibrotic activity in mice receiving repeated subcutaneous injections of bleomycin, a widely accepted animal model of human scleroderma, and could contribute to the development. The purpose of this study is to asses the efficacy and safety of topical application of P144 in the treatment of skin fibrosis in patients with systemic sclerosis.
Systemic sclerosis or scleroderma is a multisystemic disorder characterized by the excessive
synthesis and deposition of extracellular matrix proteins that result in the fibrosis of
skin and visceral organs (including gastrointestinal tract, lungs, heart and kidneys).
The pathogenesis of scleroderma is complex and still poorly understood, but major pathways
involved in the development of the condition are microvascular and immunological
abnormalities, as well as dysregulation of fibroblast activity. One of the key molecules
involved in the pathogenesis of skin fibrosis is the TGF-β1; TGF-β1 is a cytokine directly
responsible for fibroblasts proliferation and collagen and extracellular matrix
overproduction.
The affected skin of patients with systemic sclerosis gradually becomes firm, thickened and
eventually tightly bound to underlying subcutaneous tissue (indurative phase). It loses
hair, oil, and sweat glands becoming dry and coarse. Changes begin distally in the
extremities and advance proximally. Lesions develop over a period of time varying from
months to a few years. In patients with limited scleroderma, only the skin of fingers,
hands, face and lower arms and legs is affected. On the contrary, patients with the diffuse
cutaneous disease, skin changes will become generalized, involving initially the extremities
and followed by the face and trunk. Rapid progression of these changes over a 2 to 3 year
period is usually associated with a greater risk of visceral disease. After several years of
disease, the skin may soften and return to normal thickness or become thin and atrophic.
There is currently no approved specific treatment for skin fibrosis in systemic sclerosis
neither in the European Union nor the United States of America. P144 belongs to a peptide
family that is able to inhibit TGF-β1 in both in vitro and in vivo models characterized by
excessive TGF-β1 function. Topical application of P144 exerts a preventive effect precluding
the induction of skin fibrosis and the accumulation of collagen in these animals and also
has shown its therapeutic properties reducing the skin fibrosis and soluble collagen content
in mice with established fibrosis.
The EMEA and FDA have granted P144 the orphan drug status for the treatment of systemic
sclerosis. In this study, the percentage of reduction in the soluble collagen content and
skin hardness (durometer) will be measured.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
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