A Study of the Safety, Tolerability and Prelinminary Efficacy of BD111 in Herpes Simplex Virus Type I Stromal Keratitis
NCT Number: NCT06474416
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE1
Conditions: Herpes Simplex Virus Type I Stromal Keratitis
Interventions: GENETIC: BD111 Injection (Investigative New Drug)|COMBINATION_PRODUCT: Triple-drugs therapy of HSV-1 stromal keratitis
Sponsor: Shanghai BDgene Co., Ltd.
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 16
Study Design: Allocation: NON_RANDOMIZED|Intervention Model: SEQUENTIAL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2023-09-04
Completion Date: 2025-09
Locations: Huashan Hospital, Fudan University, Shanghai, Shanghai City, 200000, China|The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China|Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 310009, China

Summary:
This Phase I study is intended to evaluate the safety, tolerability, PK/PD profiles and preliminary efficacy via corneal intrastromal administration in patients with herpes simplex virus-1 stromal keratitis (HSK), with a dose exploration of four ascending doses of BD111 (investigative drug product).

Primary Outcome Measures: Dose-limiting toxicity (DLT), DLT is defined as toxicity related to BD111 observed by the investigator and sponsor during the treatment period, specifically: a) Endophthalmitis; b) Corneal perforation; c) Hypopyon; d) Other toxicities that are significantly worse than baseline or defined as ≥ Grade 4 ocular toxicity and persist for 14 days or longer, which require trial termination after discussion with the investigator and sponsor; e) Any non-ocular Grade ≥ 3 abnormality that persists for more than 1 week or requires hospitalization for medical intervention; f) death., 12 months|Maximum tolerated dose (MTD), The highest dose at which ≤1/3 of the subjects experience DLT during the DLT observation period. The MTD dose must be confirmed in at least 6 subjects., 12 months|Recommended Phase 2 dose (RP2D), The RP2D is determined by integrating safety, pharmacokinetic, and efficacy data from the comprehensive dose escalation. Typically, the MTD (DLT incidence ≤ 1/3) is used as the RP2D when it is confirmed, or a dose lower than the MTD is selected as the RP2D based on comprehensive data., 12 months|Incidence and characteristics of adverse events (AE) and serious adverse events (SAE) during the study, AE and SAE are recorded and evaluated, including eye-related AEs after treatment, such as AE at the corneal injection site., 12 months
Secondary Outcome Measures: Tear fluid vector RNA, Tear fluid vector RNA copy numbers detected by real-time qPCR test, is one of Pharmacokinetics indicators of main components of BD111, and analysizing results will be used to evaluated the PK profile of tear fluid vector RNA and dose-response relationship of BD111., 12 months|Tear fluid vector circular DNA, Tear fluid vector circular DNA copy numbers detected by real-time qPCR test, is another Pharmacokinetics indicator of main components of BD111, and analysizing results will be used to evaluated the PK profile of tear fluid vector RNA and dose-response relationship of BD111., 12 months|Blood vector circular DNA, Real-time qPCR test will be used to detect copy number of vector circular DNA in blood, analysizing the PK profile of blood vector circular DNA and dose-response relationship of BD111., 12 months|Blood p24 protein, P24 protein concentration in blood will be assayed using ELISA p24 kit at preseted timepoints, analysizing the PK profile of Blood p24 protein., 12 months|Blood Cas9 protein, Cas9 protein concentration in blood will be assayed using ELISA p24 kit at preseted timepoints, analysizing the PK profile of Blood p24 protein., 12 months|Off-target Detection (Not applicable to comparison group), BD111 off-target test of eye swabs samples will be conducted by DNA deep sequencing at Day 0, Day6 and Day 180 post-administration., 12 months|Antibodies to BD111-related ingredients (anti-drug antibodies, no applicable to comparison group), Including: a) Anti-p24 antibody in the participants' blood samples at Day 0, Day 14, Day 28, Day 180 and Day 365; b) Anti-Cas9 antibody in the participants' blood samples at Day 0, Day 14, Day 28, Day 180 and Day 365; c) Anti-BD111 antibody in the participants' blood samples at Day 0, Day 14, Day 28, Day 180 and Day 365., 12 months|The percentage of participants with successful clearance of HSV-1 viral genome in tear at Day 14, Day 28, Day 70, Day 112, Day 180, and Day 365 post-administration, The definition of successful HSV-1 clearance: negative results in tear swab HSV-1 nucleic acid tests on two consecutive samplings (interval ≥14 days).

The definition of a negative result in tear swab HSV-1 nucleic acid test: single qPCR Ct value = 40 or "undetected", or Ct value of the first qPCR test "36 \< Ct value \< 40", and the Ct value of repetitive qPCR test is 40 or "undetected"., 12 months|The percentage of participants with failed clearance of HSV-1 viral genome in tears at Day 14, Day 28, Day 70, Day 112, Day 180, and Day 365 post-administration, The failure of HSV-1 viral genome clearance is determinated by HSV-1 positive results of qPCR test. HSV-1 positive definition of qPCR test: qPCR Ct value ≤ 36, or qPCR Ct value is "36 \< Ct value \< 40" and the Ct value of repetitive qPCR test is ≤ 36, or results of both qPCR tests are "36 \< Ct value \< 40"., 12 months|Clinical cure rate of HSK at Day 70 and Day112 post-administration, Definition of HSK clinical cure: disappearance of the subject's clinical symptoms, disappearance of active inflammatory lesions on ophthalmologic examinations, and successful clearance of the HSV-1 viral genome., 12 months|The percentage of participants with HSK recurrence at Day 180, and Day 365 post-administration, Definition of HSK recurrence: HSV-1 nucleic acid qPCR test is positive, and clinical symptoms presents again, and ophthalmic examinations find active inflammatory lesions on interventional eye., 12 months|The score change of corneal inflammation scale post-administration, The score changes of corneal inflammation scale will be essessed at Day 70, Day 112, Day 180, and Day 365 post-administration., 12 months|The improvement in best corrected visual acuity (BCVA), From baseline to Day 70, Day 112, Day 180, and Day 365 post-administration., 12 months|The improvement in corrected distance visual acuity (CDVA) post-administration, From baseline to Day 70, D11ay 2, Day 180, and Day 365 post-administration., 12 months
Other Outcome Measures: Anti-p24 antibody in blood, At Day 14, Day 28, Day 180, and Day 365 post-administration., 12 months|Anti-Cas9 antibody in blood, At Day 14, Day 28, Day 180, and Day 365 post-administration., 12 months|Anti-BD111 antibody in blood, At Day 14, Day 28, Day 180, and Day 365 post-administration., 12 months