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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 2
- 试验地点
- 6
- 主要终点
- To assess the effect of QR-313 on the exclusion (skipping) of exon 73 from COL7A1 mRNA
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 4 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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:
- •surface area of the target wound ranging from 5 to 30 cm2, located centrally in the selected 7 x 7 cm TWA.
- •exposed sub-epidermal tissue to allow absorption of the IMP.
- •no suspicion of current squamous cell carcinoma (SCC) upon visual inspection.
排除标准
- •Pregnant or breast-feeding female
- •Hemoglobin level at Screening requiring transfusion. The subject may be rescreened when the condition is considered stable.
- •Use of aminoglycosides, by any route of administration, except eye drops, 7 days or 5 half-lives, whichever is longer, prior to Baseline visit.
- •Untreated carcinoma of the TWA or history of carcinoma within 5 years prior to Screening, except adequately treated cutaneous squamous or basal cell carcinoma.
- •Life expectancy less than 6 months, as assessed by the Investigator
- •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.
- •Treatment with any systemic immunomodulators, immunosuppressants or cytotoxic chemotherapy within 2 months prior to the Baseline visit.
- •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.
- •Known hypersensitivity to oligonucleotide treatment or excipients of the IMP.
- •Bleeding disorder or condition requiring the use of anticoagulants to be confirmed by aPTT by local lab within 48 hours of first treatment.
- •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).
研究组 & 干预措施
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
干预措施: QR-313 (Drug)
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
干预措施: Placebo (Drug)
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.
干预措施: QR-313 (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
To assess the effect of QR-313 on the exclusion (skipping) of exon 73 from COL7A1 mRNA
时间窗: after 4 weeks of treatment with IMP
Absence of exon 73 in COL7A1 mRNA, detected by droplet digital polymerase chain reaction (ddPCR)
Incidence of treatment emergent adverse events/serious adverse events
时间窗: through 8 weeks after last dose of IMP (EOS)
Assessment of treatment emergent adverse events/serious adverse events
次要结局
- Assessment of wound healing and skin strength as assessed by Physician Subjective Assessment of Change (PSAC)(through 8 weeks after last dose of IMP (EOS))
- Assessment of the effect of QR-313 on the presence of collagen type VII protein and anchoring fibrils(after 8 weeks of treatment)
- Assessment of wound healing and skin strength measured in surface area (cm2)(through 8 weeks after last dose of IMP (EOS))
- Assessment of systemic exposure after topical administration of QR-313 to the target wound area (TWA)(Day 1 and after 4 and 8 weeks of treatment and EOS)
- Assessment of wound healing and skin strength as assessed by Physician Subjective Assessment of Severity (PSAS)(through 8 weeks after last dose of IMP (EOS))
- Assessment of wound healing and skin strength as assessed by Short Wound Specific Questionnaire (SWSQ)(through 8 weeks after last dose of IMP (EOS))
- Assessment of wound healing and skin strength measuring onset of (re)blistering of a healed wound(through 8 weeks after last dose of IMP (EOS))