A Multicenter, Open-label, Single Dose, Phase Ⅰ Trial to Evaluate the Safety, Tolerability and Prelinminary Efficacy of BD111 in Patients With Herpes Simplex Virus Type I Stromal Keratitis in China
Trial Snapshot
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- Enrollment
- 16
- Locations
- 3
- Primary Endpoint
- Dose-limiting toxicity (DLT)
Study Overview
Brief 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).
Detailed Description
Herpes simplex keratitis is an infectious diseases of the cornea that is primarily caused by Herpes Simplex Virus 1 (HSV-1). The stromal type, also known as HSV-1 stromal keratitis (HSK), is characterized by recurrent or chronic inflammation attributed to residual virus-triggered antigen-antibody-complement cascade reactions. BD111 is a lentivirus-like particle that is an active drug substance delivering gRNA-expressing cassettes and SpCas9 mRNA.The mechanism of action (MOA) is based on CRISPR/Cas9 gene editing technology.
This is a multicenter, open-label, dose-escalation, Phase I trial to evaluate the safety, tolerability, PK/PD profiles and preliminary efficacy of BD111 in patients with herpes simplex virus-1 stromal keratitis (HSK) in China. About 16 patients will be enrolled, dividing into open-label, four dose groups and one positive control (triple-drugs therapy) group. A rapid titration dose group combined with "3+3" dose escalation is designed for dose exploration.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participants must meet all of the following inclusion criteria to be enrolled in this study
- •Aged 18 to 70 years old;
- •Clinically diagnosed patients with recurrent herpes simplex virus type I stromal keratitis (HSK). Definition of recurrence: the patient had been diagnosed with HSK and received "local antiviral eye drugs and oral antiviral drugs + local glucocorticoid eye drops" for 3 weeks with successful clinical efficacy. Before enrollment, the clinical recurrence of HSK occurred again with symptoms including tearing, photophobia, pain, blurred vision and foreign body sensation, and signs as recurrence of active inflammatory lesions examined by slit lamp;
- •HSV-1 nucleic acid test (qPCR method) positive;
- •No use of other systemic antiviral drugs or corticosteroids within 48 hours before enrollment;
- •No systemic immune diseases;
- •Good eyelid structure and blinking function;
- •Eye structure and function assessment showing potential for visual recovery;
- •No retinal detachment;
- •No history of corneal trauma;
- •The best visual acuity in the fellow eye (BCVA) ≥ 38 (ETDRS);
- •Fertile males or females must use highly effective contraceptive methods, such as, oral contraceptives, intrauterine devices, abstinence, or barrier contraception combined with spermicides, during the trial and continue contraception for 12 months after administration;
- •Participants voluntarily join the study, sign an informed consent form, have good compliance, and cooperate with follow-up visits.
Exclusion Criteria
- •Patients with any of the following conditions cannot be enrolled in this study
- •Active ocular infection caused by other pathogens in the target eye or the fellow eye within 30 days before enrollment, including but not limited to infectious conjunctivitis, keratitis, scleritis, and endophthalmitis;
- •Patients with bilateral viral keratitis
- •Previous corneal transplant surgery in the study eye;
- •Any medicine or food allergic history;
- •Absence of tear film and blinking function;
- •Severe dry eye disease;
- •Ocular surface tumor;
- •Patients with systemic autoimmune diseases;
- •Signs of systemic infection before enrollment, including fever and receiving antibiotic treatment (systemic infection in this trial is defined as abnormal values in white blood cells, lymphocytes, and neutrophils in routine blood tests);
- •Severe diseases in the major organs including but not limited to cardiovascular, lung, liver, kidney, or other uncontrolled diseases;
- •HIV infection;
- •Pregnant and lactating women (pregnancy in this trial is defined as a positive urine or blood pregnancy test);
- •Participation in other drug or medical device clinical trials at present;
- •Alcohol or drug abuse;
- •Lack of compliance with the trial or the ability to sign an informed consent form;
- •Other situations deemed unsuitable for participation in the trial by the investigator.
Outcomes
Primary Outcomes
Dose-limiting toxicity (DLT)
Time Frame: 12 months
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.
Maximum tolerated dose (MTD)
Time Frame: 12 months
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.
Recommended Phase 2 dose (RP2D)
Time Frame: 12 months
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.
Incidence and characteristics of adverse events (AE) and serious adverse events (SAE) during the study
Time Frame: 12 months
AE and SAE are recorded and evaluated, including eye-related AEs after treatment, such as AE at the corneal injection site.
Secondary Outcomes
- Tear fluid vector RNA(12 months)
- Tear fluid vector circular DNA(12 months)
- Antibodies to BD111-related ingredients (anti-drug antibodies, no applicable to comparison group)(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(12 months)
- Blood vector circular DNA(12 months)
- Blood p24 protein(12 months)
- Blood Cas9 protein(12 months)
- Off-target Detection (Not applicable to comparison group)(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(12 months)
- Clinical cure rate of HSK at Day 70 and Day112 post-administration(12 months)
- The percentage of participants with HSK recurrence at Day 180, and Day 365 post-administration(12 months)
- The score change of corneal inflammation scale post-administration(12 months)
- The improvement in best corrected visual acuity (BCVA)(12 months)
- The improvement in corrected distance visual acuity (CDVA) post-administration(12 months)