Clinical trial NCT03605069: A Double-blind, Randomized, Intra-subject Placebo-controlled, Multicenter, Multiple Dose Study, Evaluating Safety, Proof of Mechanism, Preliminary Efficacy and Systemic Exposure in Subjects With Confirmed DDEB or RDEB Diagnosis With One or More Pathogenic Mutations in Exon 73 in the COL7A1 Gene
Official title: A First in Human, Double-blind, Randomized, Intra-subject Placebo-controlled, Multiple Dose Study of QR-313 Evaluating Safety, Proof of Mechanism, Preliminary Efficacy and Systemic Exposure in Subjects With DDEB or RDEB Due to Mutation(s) in Exon 73 of the COL7A1 Gene
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Epidermolysis Bullosa Dystrophica, Recessive
Epidermolysis Bullosa Dystrophica, Dominant
Keywords: Recessive Dystrophic Epidermolysis Bullosa
EB
COL7A1
RNA Therapies
Antisense oligonucleotide
Exon skipping
WINGS
Topical treatment
RDEB
Exon 73
Mutations in exon 73
Dominant Dystrophic Epidermolysis Bullosa
DDEB
Lead sponsor: Phoenicis Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-07-30
Enrollment: 2
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: intra-subject, placebo-controlled
Primary purpose: TREATMENT

Brief summary: A double-blind, randomized, intra-subject placebo-controlled, multicenter, multiple dose study, evaluating safety, proof of mechanism, preliminary efficacy and systemic exposure in subjects with confirmed DDEB or RDEB diagnosis with one or more pathogenic mutations in exon 73 in the COL7A1 gene.

Detailed description: This clinical trial will evaluate the safety and tolerability, proof of mechanism, systemic exposure and preliminary efficacy following topical application of QR-313 to subjects with confirmed DDEB or RDEB with one or more pathogenic mutations in exon 73 in the COL7A1 gene.

Up to two Target Wound Areas (TWAs) per subject will be selected and randomized. Each TWA will be treated with IMP for 8 weeks, either QR-313 or matching placebo. All subjects will continue to be followed up for 8 weeks post last dose.

Subjects will be monitored through home visits and site visits. An imaging system will be used to assess the target wound at all home and study site visits.

QR-313 is a 21-nucleotide antisense oligonucleotide (AON) designed to hybridize to a specific sequence in the COL7A1 pre-messengerRNA (pre-mRNA).

Eligibility criteria: Inclusion Criteria:

1. Male or female, ≥ 4 years of age at Screening with a clinical diagnosis of DDEB or RDEB and at least one pathogenic mutation in exon 73 of the COL7A1 gene.
2. Have at least one TWA, ie, a skin area of 7 x 7 cm that ishows no signs of local infection, and contains a target wound that is either new or shows dynamic wound healing and complies to the following additional criteria:

   1. surface area of the target wound ranging from 5 to 30 cm2, located centrally in the selected 7 x 7 cm TWA.
   2. exposed sub-epidermal tissue to allow absorption of the IMP.
   3. no suspicion of current squamous cell carcinoma (SCC) upon visual inspection.

Exclusion Criteria:

1. Pregnant or breast-feeding female
2. Hemoglobin level at Screening requiring transfusion. The subject may be rescreened when the condition is considered stable.
3. Use of aminoglycosides, by any route of administration, except eye drops, 7 days or 5 half-lives, whichever is longer, prior to Baseline visit.
4. Untreated carcinoma of the TWA or history of carcinoma within 5 years prior to Screening, except adequately treated cutaneous squamous or basal cell carcinoma.
5. Life expectancy less than 6 months, as assessed by the Investigator
6. Current or known history of clinically significant hepatic or renal disease, that in the opinion of the Investigator, could impact subject safety or study participation.
7. Treatment with any systemic immunomodulators, immunosuppressants or cytotoxic chemotherapy within 2 months prior to the Baseline visit.
8. Use of any investigational drug or device within 28 days or 5 half-lives of the Baseline visit, whichever is longer, or plans to participate in another study of a drug or device during the study period. The washout of 5 half-lives does not apply to gene and cell therapy.
9. Known hypersensitivity to oligonucleotide treatment or excipients of the IMP.
10. Bleeding disorder or condition requiring the use of anticoagulants to be confirmed by aPTT by local lab within 48 hours of first treatment.
11. Use of systemic or topical steroids within 1 month prior to the baseline visit (inhaled and ophthalmic drops of corticosteroids or low dose topical solution of budesonide for esophagial strictures may be allowed).

Primary outcomes:
measure: Incidence of treatment emergent adverse events/serious adverse events
timeFrame: through 8 weeks after last dose of IMP (EOS)
measure: To assess the effect of QR-313 on the exclusion (skipping) of exon 73 from COL7A1 mRNA
timeFrame: after 4 weeks of treatment with IMP
Secondary outcomes:
measure: Assessment of wound healing and skin strength measured in surface area (cm2)
timeFrame: through 8 weeks after last dose of IMP (EOS)
measure: Assessment of wound healing and skin strength as assessed by Physician Subjective Assessment of Severity (PSAS)
timeFrame: through 8 weeks after last dose of IMP (EOS)
measure: Assessment of wound healing and skin strength as assessed by Physician Subjective Assessment of Change (PSAC)
timeFrame: through 8 weeks after last dose of IMP (EOS)
measure: Assessment of wound healing and skin strength measuring onset of (re)blistering of a healed wound
timeFrame: through 8 weeks after last dose of IMP (EOS)
measure: Assessment of wound healing and skin strength as assessed by Short Wound Specific Questionnaire (SWSQ)
timeFrame: through 8 weeks after last dose of IMP (EOS)
measure: Assessment of systemic exposure after topical administration of QR-313 to the target wound area (TWA)
timeFrame: Day 1 and after 4 and 8 weeks of treatment and EOS
measure: Assessment of the effect of QR-313 on the presence of collagen type VII protein and anchoring fibrils
timeFrame: after 8 weeks of treatment
measure: Assessment of the effect of QR-313 on the presence of collagen type VII protein and anchoring fibrils
timeFrame: after 8 weeks of treatment
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University School of Medicine, LPCH
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Minneapolis
country: United States
facility: Journey Clinic, Center for Pediatric Blood and Marrow Transplantation
state: Minnesota
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Paris
country: France
facility: Hopital Necker Enfants Malades
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
Study officials:
affiliation: Phoenicis Therapeutics
name: Clinical Operations
role: STUDY_DIRECTOR
References:
citation: Miah KM, Hyde SC, Gill DR. Emerging gene therapies for cystic fibrosis. Expert Rev Respir Med. 2019 Aug;13(8):709-725. doi: 10.1080/17476348.2019.1634547. Epub 2019 Jun 27.