Study of Immune Tolerance and Capacity for Wound Healing of Patients With Recessive Dystrophic Epidermolysis Bullosa (RDEB)

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by Institut National de la Santé Et de la Recherche Médicale, France
Sponsor:
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier:
NCT01874769
First received: April 3, 2013
Last updated: December 17, 2013
Last verified: December 2013
  Purpose

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is one of the most severe rare inherited skin disorders affecting children and adults. Current medical care protocols for RDEB patients are limited to palliative procedures to treat blistering and erosive lesions, wounds, and severe local and systemic complications such as fusion and contracture of the digits, skin cancer, esophageal stricture, severe anemia, infections, malnutrition and growth retardation. However, current medical treatments still cannot prevent the recurrence of the lesions arising from defective expression of type VII collagen (COL7A1), the main constituent of anchoring fibrils which form essential structures for dermal-epidermal adherence.

The purpose of this study is to investigate the capacity of keratinocytes and fibroblasts to repair skin wounds in patients suffering from Recessive Dystrophic Epidermolysis Bullosa (RDEB).


Condition Intervention
Recessive Dystrophic Epidermolysis Bullosa
Other: Blood collection
Other: Skin biopsies

Study Type: Observational
Study Design: Observational Model: Cohort
Official Title: Study of Immune Tolerance and Capacity for Wound Healing of Patients With Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Resource links provided by NLM:


Further study details as provided by Institut National de la Santé Et de la Recherche Médicale, France:

Primary Outcome Measures:
  • Determination of the proliferative capacity of keratinocytes and fibroblasts in characterized RDEB patients [ Time Frame: Month 23 ] [ Designated as safety issue: No ]
    Populations of keratinocytes and fibroblasts isolated from punch biopsies will be analyzed for their proliferative capacity.


Secondary Outcome Measures:
  • Clinical evaluation and scoring [ Time Frame: Month 9 ] [ Designated as safety issue: No ]
    Clinical evaluation and scoring will be assessed using The Birmingham Epidermolysis Bullosa Severity score.

  • Identification of COL7A1 mutations [ Time Frame: Month 9 ] [ Designated as safety issue: No ]
    COL7A1 mutations will be screened by direct sequencing of peripheral blood DNA using a set of primers designed to sequence the 118 COL7A1 exons and their intronic junctions.

  • Assessment of type VII collagen expression and anchoring fibrils formation in the skin [ Time Frame: Month 9 ] [ Designated as safety issue: No ]
    Punch biopsies of the patient skin will be taken and processed for cell culture (keratinocytes and fibroblasts) and for histological and ultrastructural analyses.


Other Outcome Measures:
  • Identification of circulating antibodies against type VII collagen and quantification of the frequency of reactive T-lymphocytes against type VII collagen [ Time Frame: Month 9 ] [ Designated as safety issue: No ]
    Humoral and cytotoxic immune response against full-length type VII collagen will be assessed by ELISA and ELISPOT assays respectively.

  • Determination of the likelihood for the patient of developing an immune response to type VII collagen [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    High resolution HLA genotyping will be performed from patient's DNA. Patient prediction of non‐self epitopes on WT collagen VII, based on the patient's COL7A1 mutations and their HLA typing will be performed in silico.


Biospecimen Retention:   Samples With DNA

All patients will have a blood sample of 5 ml on EDTA, 10 ml on heparin and 5 ml on dry tube collected for genomic DNA extraction to identify or verify COL7A1 mutations: mutation screening of the patients will be performed to identify COL7A1 mutations on both alleles. 2) HLA genotyping: patients selected on the clinical and molecular criteria will be HLA-genotyped by PCR to determine the likelihood of an immune response to the type VII collagen wild-type protein. A 5-mm punch skin biopsy performed under local anaesthesic will be undertaken during visit 1 for diagnostic purposes .The consequences of COL7A1 mutations on collagen VII protein expression will be determined, if not performed previously. Two additional 5-mm punch skin biopsies will be taken from different areas from up to 10 patients during the second visit. Keratinocytes and fibroblasts will be expanded and stored in vapor-phase liquid-nitrogen.


Estimated Enrollment: 30
Study Start Date: June 2013
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Blood collection and skin biopsies Other: Blood collection
  • 5 ml of blood on dry tube: Verification of the absence of auto-antibodies to type VII collagen.
  • 10 ml of blood sample on heparin: Verification of the absence of circulating reactive T-Lymphocytes clones to type VII collagen
  • 5 ml of Blood samples on ethylenediaminetetraacetic acid (EDTA): HLA genotyping of patient selected on the clinical and molecular criteria.
Other: Skin biopsies
  • A 5-mm punch skin biopsy in the groin region performed under local anaesthesic will be undertaken during visit 1.
  • During the second visit, two additional 5-mm punch skin biopsies will be taken to assess stem cells proliferative capacity in 10 shortlisted patients

Detailed Description:

In the perspective of future therapeutic interventions, which could involve protein, cellular and/or gene therapy, it is essential to investigate RDEB patients with regards to their immune tolerance to type VII collagen and their capacity of their cells for tissue reconstruction.

  Eligibility

Ages Eligible for Study:   7 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Adults and children with RDEB

Criteria

Inclusion Criteria:

  • Confirmed molecular diagnosis of recessive dystrophic epidermolysis bullosa, established for both alleles;
  • Non severe generalized clinical form of RDEB;
  • Presence of type VII collagen on skin biopsy and/or western-blot analysis detected with a set of specific antibodies;
  • Presence of intact skin areas without blisters, infection or erosion;
  • Absence of hospitalization related to EB condition;
  • Patients and their parents when applicable should be able and willing to return for follow up;
  • Patients should be able and willing to give signed informed consent. For patients who are minor, informed consent will be signed by a legally authorized representative, as well as an assent form by the minor patient.
  • Ability to undergo local anesthesia.

Exclusion Criteria:

  • Severity of disease and presence of ill-prognostic features:

    1. Premature termination codon in the noncollagenous (NC1) domain of COL7A1 on both alleles;
    2. Absence of detectable type VII collagen expression on skin biopsy and Western blot analysis from cultured cells;
  • Underlying conditions, diseases or active infections likely to increase the risk of complications or to interfere with the biological investigations:

    1. History of current or previous skin cancer (Squamous cell carcinoma or other malignant skin cancer);
    2. Current infectious diseases, including systemic infections and known positive HIV serology (Kaposi's sarcoma), hepatitis B and C;
    3. History of current psychological or psychiatric disease;
    4. Absence of an adequate familial and social support;
    5. History of current or previous organ diabetes mellitus;
    6. Non corrected severe anemia (Hemoglobin level: < 8 g/ml);
    7. Non corrected iron deficiency;
    8. History of significant allergy to an anaesthetic procedure
    9. Patient currently receiving anticoagulant or anti-aggregation treatment;
    10. Participation in another clinical trial or therapy protocol for RDEB at the time of study inclusion
    11. Positive pregnancy urinary test or lactating women
  • Not affiliated to the national social security/health service beneficiary and families with beneficiary children.
  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: NCT01874769

Contacts
Contact: Alain Hovnanian, Prof +33 1 71 19 63 95 alain.hovnanian@inserm.fr

Locations
France
Inserm U781 Service de Génétique Necker Hospital for sick children Recruiting
Paris, France, 75743/ Cedex 15
Principal Investigator: Alain Hovnanian, Prof, MD, PhD         
Service de dermatologie Necker Hospital for sick children Recruiting
Paris, France, 75743 Cedex 15
Contact: Christine Bodemer, Prof         
Principal Investigator: Alain Hovnanian, Prof, MD, PhD         
United Kingdom
Guy's and ST Thomas NHS Foundation trust/Guy's Hospital Recruiting
London, United Kingdom, SE19RT
Principal Investigator: John McGrath, Prof, MD, PhD         
Sponsors and Collaborators
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
Principal Investigator: Alain Hovnanian, Prof National Institut of health and medical research
  More Information

No publications provided

Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT01874769     History of Changes
Other Study ID Numbers: C12-22, 2012-A01051-42
Study First Received: April 3, 2013
Last Updated: December 17, 2013
Health Authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:
RDEB
COL7A1
Collagen VII

Additional relevant MeSH terms:
Epidermolysis Bullosa
Epidermolysis Bullosa Dystrophica
Collagen Diseases
Congenital Abnormalities
Connective Tissue Diseases
Genetic Diseases, Inborn
Skin Abnormalities
Skin Diseases
Skin Diseases, Genetic
Skin Diseases, Vesiculobullous

ClinicalTrials.gov processed this record on October 29, 2014