Tolerability and Bioavailability of the P144 Peptide Inhibitor of TGF-β1 After Topical Administration in Healthy Volunteers

This study has been completed.
Sponsor:
Collaborator:
Digna Biotech S.L.
Information provided by:
ISDIN
ClinicalTrials.gov Identifier:
NCT00656825
First received: April 7, 2008
Last updated: November 4, 2008
Last verified: November 2008
  Purpose

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 assess the tolerability and safety of topical application of P144 in healthy volunteers.


Condition Intervention Phase
Healthy
Drug: P144 cream
Drug: Placebo
Phase 1

Study Type: Interventional
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.

Resource links provided by NLM:


Further study details as provided by ISDIN:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 36
Study Start Date: March 2007
Study Completion Date: June 2007
Primary Completion Date: June 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Placebo
Placebo will be randomly given to 4 subjects in each panel

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Capable of understanding and willing to provide signed and dated written voluntary informed consent before any protocol specific procedures are performed.
  • Age between 18 and 45 years old
  • Skin phenotype I to IV following Fitzpatrick's classification scale
  • BMI between 20-29 kg/sqm
  • Not clinically relevant alterations in: arterial pressure, cardiac frequency, analytical values (Hematology, Biochemistry, Urianalysis, Coagulation, Serology, Toxics)

Exclusion Criteria:

  • Pregnany or lactancy
  • Allergy to any medication
  • Subjects with skin illnesses or systemic illnesses with skin afectation
  • History of drug abuse or regular consumption of alcohol
  • Participation in other clinical trials 3 months before the signature of the informed consent
  • UV exposure or sun exposure on the zone to be treated
  • History of skin hypersensitivity
  • Chronic treatment with anti-inflammatories or anti-histaminics
  • Treatment with corticoids on the previous month
  • Hyperpigmentation on the zone to be treated
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00656825

Locations
Spain
Hospital Universitario Puerta de Hierro
Madrid, Spain, 28035
Clínica Universitaria de Navarra
Pamplona, Spain, 31008
Sponsors and Collaborators
ISDIN
Digna Biotech S.L.
Investigators
Principal Investigator: Belén Ruiz, MD Hospital Universitario Puerta de Hierro
Principal Investigator: Belén Sádaba, MD Clínica Universitaria de Navarra
  More Information

No publications provided

Responsible Party: ISDIN
ClinicalTrials.gov Identifier: NCT00656825     History of Changes
Other Study ID Numbers: NAFB001-SS-01, 2006-002755-33
Study First Received: April 7, 2008
Last Updated: November 4, 2008
Health Authority: Spain: Ministry of Health and Consumption

Keywords provided by ISDIN:
P144
TGF-β1
Healthy volunteers
Cutaneous tolerability
Skin fibrosis
systemic scleroderma
systemic sclerosis
Cutaneous Tolerability
Safety

ClinicalTrials.gov processed this record on August 21, 2014