Clinical trial NCT04153630: Safety Study and Preliminary Efficacy of Infusion Haploidentical Mesenchymal Stem Cells Derived From Bone Marrow for Treating Recessive Dystrophic Epidermolysis Bullosa
Official title: Safety Study and Preliminary Efficacy of Infusion Haploidentical Mesenchymal Stem Cells Derived From Bone Marrow for Treating Recessive Dystrophic Epidermolysis Bullosa
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Epidermolysis Bullosa Dystrophica, Recessive
Lead sponsor: Instituto de Investigación Hospital Universitario La Paz
Sponsor class: OTHER
Collaborators: name: Universidad Carlos III Madrid (TERMeG)
name: St John's Institute of Dermatology Kings College London
name: Instituto de Salud Carlos III
name: DEBRA
name: CIBER Enfermedades raras
First posted: 2019-11-06
Enrollment: 9
Sex: ALL
Minimum age (years): 12
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Phase I / II pilot clinical trial, to evaluate the safety and preliminary efficacy of the systemic infusion of mesenchymal stem cells derived from bone marrow (BM-MSCs) from a haploidentical donor to improve the healing process and / or the mucocutaneous fragility phenotype associated with EBDR.

Detailed description: The Main Objective is to evaluate the safety and therapeutic efficacy of haploidentical MSCs derived from bone marrow administered by intravenous injection for the treatment of patients with RDBS. The assessment of the symptomatic improvement of the treated patients will be made regarding the baseline situation and the response to treatment at the biochemical, histological and molecular level.

Secondary Objectives:

Describe the clinical and molecular phenotype of the mucocutaneous involvement of patients, including the characterization of the mutations responsible for the disease.

Study drug: Allogenic mesenchymal cells (haploidentical) derived from bone marrow and expanded.

Method of administration: Systemic / Intravenous Administration dose: 2-3x10e6 BM-MSC / Kg. Weekly dose for three consecutive weeks

Follow-up period: 12 months after the infusion. However, patients will be monitored outside the clinical trial over a 5-year period

Eligibility criteria: Inclusion Criteria:

1. Male and female patients ≥ 12 months and ≤ 18 years of age at the time of inclusion in the study.
2. Patients with a clinical, molecular and genetic diagnosis of EBDR.
3. Patients with presence of the NC-1 domain of type VII collagen, in skin biopsies and/or Western-Blot, detected with a battery of specific antibodies.
4. Patients with a haploidentical donor.
5. Subjects with a severity score\> 20 according to "The Birmingham Epidermolysis Bullosa Severity Score".
6. Minor subjects whose representative / legal guardian has voluntarily signed the informed consent before the first intervention of the study.
7. In the case of mature minors (12-17 years of age), in addition to the consent signed by the legal guardian, the consent of the minor will be obtained.
8. Women with reproductive capacity must have a negative pregnancy test at the time of inclusion and must agree to use highly effective contraceptive methods (diaphragms plus spermicide or male condom plus spermicide, oral contraceptive combined with a second method contraceptive implant, contraceptive injectable, permanent intrauterine device, sexual abstinence or partner with vasectomy) during their participation in the study until 30 days after the last visit.
9. Males should agree to use a double-barrier contraceptive method (condom plus spermicide or diaphragm plus spermicide) during their participation in the study and up to 30 days after the last dose of the study drug, or the male patient or his Female partners must be surgically sterilized or the female partner must be postmenopausal.
10. The patient must be able to attend all study visits and comply with all study procedures.

Exclusion Criteria:

1. Subjects who for medical reasons can not be moved to the University Hospital La Paz in Madrid.
2. Subjects who have received immunotherapy including oral corticosteroids (\> 15 mg / day) for more than 1 week (excluding inhaled and ophthalmic preparations) or chemotherapy 8 days prior to inclusion in the study. The inclusion of the patient is understood from the signing of the informed consent.
3. Subjects with a known allergy to any of the components of the investigational product (including penicillin and streptomycin), or who can not receive treatment with antihistamines and/or corticosteroids.
4. Subjects with signs of active systemic infection at the time of inclusion in the study. In any case, according to the researcher's criteria, the patient can be reevaluated for inclusion in the study after improvement of the infectious pathology.
5. Subjects with a history or signs of malignancy, including cutaneous squamous cell carcinoma.
6. Subjects with circulating anti-C7 antibodies and anti-C7 antibodies deposited in the dermo-epidermal junction detected in skin biopsies by indirect immunofluorescence.
7. Pregnant women at the time of inclusion or women of childbearing age who do not practice abstinence or employ acceptable means of contraception, as determined by the investigator during the trial.
8. Biochemical abnormalities at the time of inclusion: albumin \<2.5 g / dL, Hemoglobin \<7.5 g / dL.
9. Subjects to whom other investigational drugs have been administered in the 90 days prior to the treatment phase.
10. Subjects who are unable to understand the information sheet and unable to sign the informed consent.

Primary outcomes:
measure: Safety evaluation: Incidence of Treatment-Emergent Adverse Events as assessed by protocol.
timeFrame: 1 year after infusion
Secondary outcomes:
measure: Cutaneous mechanical resistance
timeFrame: 2 year after infusion
measure: Skin surface affected
timeFrame: 2 year after infusion
measure: Number of blisters
timeFrame: 2 year after infusion
measure: Non-specific general markers of systemic inflammation: white blood cell count
timeFrame: 2 year after infusion
measure: Non-specific general markers of systemic inflammation: Negative acute phase reactant (albumin)
timeFrame: 2 year after infusion
measure: Non-specific general markers of systemic inflammation: Negative acute phase reactants (pre-albumin, transferrin and retinol-binding protein)
timeFrame: 2 year after infusion
measure: Non-specific general markers of systemic inflammation: Positive acute phase reactants (c-reactive protein and fibrinogen)
timeFrame: 2 year after infusion
measure: Non-specific general markers of systemic inflammation: Positive acute phase reactants (ferritin)
timeFrame: 2 year after infusion
measure: Severity index according to "The Birmingham Epidermolysis Bullosa Severity Score" before and after treatment
timeFrame: 2 year after infusion
measure: Severity index according to "The Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) before and after treatment
timeFrame: 2 year after infusion
measure: Expression of Collagen VII (C7) in skin biopsy
timeFrame: 2 year after infusion
measure: Analysis of anchoring fibrils
timeFrame: 2 year after infusion
measure: Variation of pain respect to baseline status: Visual Analog Scale
timeFrame: 2 year after infusion
measure: Modification in itching perceived
timeFrame: 2 year after infusion
measure: Change in quality of life of patient: European Quality of Life-5 Dimensions-5 level (EUROQL-5D)
timeFrame: 2 year after infusion
measure: Evaluation of circulating anti-C7 antibodies
timeFrame: 2 year after infusion
measure: Change in general condition of the patient
timeFrame: 2 year after infusion
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
Study officials:
References: