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

• ClinicalTrials.gov Identifier: NCT03605069
• Recruitment Status: Terminated
• First Posted: July 30, 2018
• Last Update Posted: August 25, 2021
• Sponsor: Phoenicis Therapeutics
• Information provided by (Responsible Party): Phoenicis Therapeutics

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Epidermolysis Bullosa Dystrophica, Recessive; Epidermolysis Bullosa Dystrophica, Dominant	Drug: QR-313; Drug: Placebo	Phase 1; Phase 2

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: intra-subject, placebo-controlled
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: July 2, 2018
• Actual Primary Completion Date: December 17, 2018
• Actual Study Completion Date: December 17, 2018

Arms and Interventions

Arm	Intervention/treatment
First TWA (A); In each subject up to two target wound areas (TWA) are randomized, one each to active treatment or placebo. In the first arm; randomization of the first selected TWA to active treatment or placebo	Drug: QR-313; QR-313 will be applied topically once daily for 8 weeks of treatment.; Drug: Placebo; Placebo will be applied topically once daily for 8 weeks of treatment.
Second TWA (B); In each subject, in the second arm; allocation of the second selected target wound area (TWA) to the alternative treatment. Second arm in the same subject as the first arm.	Drug: QR-313; QR-313 will be applied topically once daily for 8 weeks of treatment.; Drug: Placebo; Placebo will be applied topically once daily for 8 weeks of treatment.

Outcome Measures

Primary Outcome Measures :

1. Incidence of treatment emergent adverse events/serious adverse events [ Time Frame: through 8 weeks after last dose of IMP (EOS) ]
   Assessment of treatment emergent adverse events/serious adverse events
2. To assess the effect of QR-313 on the exclusion (skipping) of exon 73 from COL7A1 mRNA [ Time Frame: after 4 weeks of treatment with IMP ]
   Absence of exon 73 in COL7A1 mRNA, detected by droplet digital polymerase chain reaction (ddPCR)

Secondary Outcome Measures :

1. Assessment of wound healing and skin strength measured in surface area (cm2) [ Time Frame: through 8 weeks after last dose of IMP (EOS) ]
   Wound size (surface area in cm2)
2. Assessment of wound healing and skin strength as assessed by Physician Subjective Assessment of Severity (PSAS) [ Time Frame: through 8 weeks after last dose of IMP (EOS) ]
   Wound severity as assessed by Physician Subjective Assessment of Severity (PSAS), a 3-point Likert static scale that classifies a wound in mild, moderate or severe
3. Assessment of wound healing and skin strength as assessed by Physician Subjective Assessment of Change (PSAC) [ Time Frame: through 8 weeks after last dose of IMP (EOS) ]
   Wound change in severity as assessed by Physician Subjective Assessment of Change (PSAC), a 3-point Likert static scale that classifies a wound as mild, moderate or severe.
4. Assessment of wound healing and skin strength measuring onset of (re)blistering of a healed wound [ Time Frame: through 8 weeks after last dose of IMP (EOS) ]
   Onset of (re)blistering of a healed wound
5. Assessment of wound healing and skin strength as assessed by Short Wound Specific Questionnaire (SWSQ) [ Time Frame: through 8 weeks after last dose of IMP (EOS) ]
   Wound status as assessed by Short Wound Specific Questionnaire (SWSQ) addressing three domains: pruritus, pain, and inflammation. Pruritus and pain are recorded as a Patient Reported Outcome (PRO) measure. Inflammation is reported as an Observer Reported Outcome (ObsRO) measure.
6. Assessment of systemic exposure after topical administration of QR-313 to the target wound area (TWA) [ Time Frame: Day 1 and after 4 and 8 weeks of treatment and EOS ]
   Serum levels of QR-313
7. Assessment of the effect of QR-313 on the presence of collagen type VII protein and anchoring fibrils [ Time Frame: after 8 weeks of treatment ]
   Presence of collagen type VII protein expression (IIF microscopy)
8. Assessment of the effect of QR-313 on the presence of collagen type VII protein and anchoring fibrils [ Time Frame: after 8 weeks of treatment ]
   Presence of anchoring fibrils (TEM)

Eligibility Criteria

• Ages Eligible for Study: 4 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

United States, California

Stanford University School of Medicine, LPCH

Palo Alto, California, United States, 94305

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Minnesota

Journey Clinic, Center for Pediatric Blood and Marrow Transplantation

Minneapolis, Minnesota, United States, 55454

United States, Ohio

Cincinnati Children's Hospital

Cincinnati, Ohio, United States, 15005

France

Hopital Necker Enfants Malades

Paris, France, 75015

Spain

Hospital Universitario La Paz

Madrid, Spain, 28046

Sponsors and Collaborators

Phoenicis Therapeutics

Investigators

• Study Director: Clinical Operations; Phoenicis Therapeutics

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Phoenicis Therapeutics
• ClinicalTrials.gov Identifier: NCT03605069
• Other Study ID Numbers: PQ-313-002; 2017-004806-17 ( EudraCT Number )
• First Posted: July 30, 2018
• Last Update Posted: August 25, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Phoenicis Therapeutics:

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

Additional relevant MeSH terms:

Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Skin Abnormalities; Congenital Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases; Skin Diseases, Vesiculobullous; Collagen Diseases; Connective Tissue Diseases