Tolerability and Bioavailability of the P144 Peptide Inhibitor of TGF-β1 After Topical Administration in Healthy Volunteers
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
|Official Title:||Multicentre, Placebo-Controlled, Multi-Dosis, Phase I Clinical Trial to Evaluate the Tolerability and Bioavailability of TGF β1 Inhibitor Peptide 144 After Topical Administration in Healthy Volunteers.|
- Tolerability evaluation was performed through the specific cutaneous tolerability visual scale of Frosch and Kligman. [ Time Frame: Twenty-one days ] [ Designated as safety issue: No ]
- Safety assessment was carried out by studying vital signs, physical examination, by performing laboratory tests, electrocardiogram and reporting any adverse events experienced. Bioavailability of P 144 in serum. [ Time Frame: Twenty-one days ] [ Designated as safety issue: Yes ]
|Study Start Date:||March 2007|
|Study Completion Date:||June 2007|
|Primary Completion Date:||June 2007 (Final data collection date for primary outcome measure)|
Active Comparator: Panel I
The first 12 subjects will be selected and ranodmized in order to receive the first treatment dose of 100 μg/mL or placebo in a 8:4 ratio
Drug: P144 cream
P144 cream will be given at a dose of 100 μg/mL
Active Comparator: Panel II
The second 12 subjects will be selected and randomized in order to receive the second treatment dose of 200 μg/mL or placebo in a 8:4 ratio
Drug: P144 cream
P144 cream will be given at a dose of 200 μg/mL
Active Comparator: Panel III
The third 12 subjects will be selected and randomized in order to receive the third treatment dose of 300 μg/mL or placebo in a 8:4 ratio
Drug: P144 cream
P144 cream will be given at a dose of 300 μg/mL
Placebo Comparator: Placebo
Patients from each panel will be given placebo in a 4:8 ratio.
Placebo will be randomly given to 4 subjects in each panel
Three different formulations of DIGNA P144 cream (containing 100 μg/mL, 200 μg/mL and 300 μg/mL) will be tested in healthy volunteers. Tolerability evaluation is performed through the specific cutaneous tolerability visual scale of Frosch and Kligman. Safety assessment is carried out by studying vital signs, physical examination, by performing laboratory tests, electrocardiogram and reporting any adverse events experienced. This is the first time that P144 will be administered in humans. The topical route has been chosen since the indication for which P144 is going to be clinically developed will be cutaneous sclerosis associated to scleroderma.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00656825
|Hospital Universitario Puerta de Hierro|
|Madrid, Spain, 28035|
|Clínica Universitaria de Navarra|
|Pamplona, Spain, 31008|
|Principal Investigator:||Belén Ruiz, MD||Hospital Universitario Puerta de Hierro|
|Principal Investigator:||Belén Sádaba, MD||Clínica Universitaria de Navarra|