Safety and Efficacy of CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy to Treat Refractory Viral Keratitis

• ClinicalTrials.gov Identifier: NCT04560790
• Recruitment Status: Active, not recruiting
• First Posted: September 23, 2020
• Last Update Posted: May 26, 2021
• Sponsor: Shanghai BDgene Co., Ltd.
• Collaborator: Eye & ENT Hospital of Fudan University
• Information provided by (Responsible Party): Shanghai BDgene Co., Ltd.

Tracking Information

• First Submitted Date: September 17, 2020
• First Posted Date: September 23, 2020
• Last Update Posted Date: May 26, 2021
• Actual Study Start Date: November 4, 2020
• Estimated Primary Completion Date: November 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 23, 2020)

• Concentration of dose limiting toxicities [ Time Frame: 24 months ]
  Observe and record AE,SAE incidence of dose limiting toxicities related with BD111 administration.
• Concentration of maximum tolerated dose [ Time Frame: 24 months ]
  Observe and record AE,SAE at maximum tolerated dose when occurs dose limiting toxicities.
• Clearance effective of HSV-1 genome [ Time Frame: 24 months ]
  Judge HSV-1 genome clearance effective according to DNA sequencing results by methods of Plaque assay,Elisa,PCR etc.
• Rate of reblindness in 6 participants with Refractory Viral Keratitis [ Time Frame: 24 months ]
  180 days after corneal surgical, calculate rate of reblindness of treated eye in 6 participants.
• Grafted corneal survival time [ Time Frame: 24 months ]
  Observe the survival time of grafted corneal in subjects, whether the grafted corneal is transparency or opacity.
• Visual improvement compared with baseline [ Time Frame: 24 months ]
  Judge the visual recovery progress according to visual examination results on day 3±1，7±2，30±7，90±14，180±21，360±31.

Original Primary Outcome Measures (submitted: September 17, 2020)

• Dose limiting toxicities [ Time Frame: 24 months ]
  Incidence of dose limiting toxicities related with BD111 administration
• Maximum tolerated dose [ Time Frame: 24 months ]
  Maximum tolerated dose determinated by occurrence of dose limiting toxicities
• HSV-1 genome clearance [ Time Frame: 24 months ]
  HSV-1 genome clearance by DNA sequencing
• rate of reblindness [ Time Frame: 24 months ]
  rate of reblindness
• biopsy survival [ Time Frame: 24 months ]
  biopsy survival
• visual recovery [ Time Frame: 24 months ]
  visual recovery according visual examination

Current Secondary Outcome Measures (submitted: September 23, 2020)

Falling of herpes virus content compared with baseline [ Time Frame: 24 months ]

Herpes virus content before and after treatment were determinated by methods of plaque assay,ELISA,PCR etc.Compare the viral content changes with baseline.

Original Secondary Outcome Measures (submitted: September 17, 2020)

virus content falling [ Time Frame: 24 months ]

changes of virus content before and after treatment were determinated by methods of plaque assay,ELISA,PCR etc.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy of CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy to Treat Refractory Viral Keratitis
• Official Title: CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy Assisted Corneal Transplantation in the Treatment of Refractory Viral Keratitis
• Brief Summary: The purpose of this study is to evaluate the safety, tolerability and efficacy of a single escalating doses of BD111 CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy administered via corneal injection in participants with refractory herpetic viral keratitis.

Detailed Description

This is an open-label, single ascending dose study of BD111 in adult (ages 18 to 70) participants with refractory herpetic viral keratitis. Approximately 6 participants will be enrolled.BD111 is a novel gene editing product designed to clear Herpes simplex virus type I (HSV-1) that results in herpetic stromal keratitis in both acute and recurrent infection models which is the leading factor for infectious blindness.

The follow-up period was 360 days, and the patients will be followed up 3±1 days, 7±2 days, 30±7 days, 90±14 days, 180±21 days, and 360+31 days after treatment.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Single group target value: Since there is no similar products approved on the market and there is no similar comparative treatment methods, the single group target value method is adopted

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Viral Keratitis
• Blindness Eye
• Herpes Simplex Virus Infection
• Cornea

Intervention

Drug: BD111 Adult single group Dose

6 Participants will receive a single group dose administered via corneal injection in the study eye.

Study Arms

Experimental: BD111 Adults single group Dose

Administered by corneal injection surgery. Dosage form:injection solution. Dose:200uL. Frequency of administration: one time injection.

Intervention: Drug: BD111 Adult single group Dose

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: September 17, 2020): 6
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 2022
• Estimated Primary Completion Date: November 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Patients (replase) with refractory keratitis caused by herpes virus type I who has had at least one time failed corneal transplant.

1. Age between 18 to 70 years.
2. No systemic immune eye disease.
3. Good eyelid structure and blink function.
4. Exists the potential of visual recovery by evaluation of ocular structure and function.
5. Identify patients who are repeatedly infected with HSV-1 virus(only under the condition that the patients are obviously suffering replase infections，corneal perforation and need corneal transplantation).
6. No retinal detachment and normal visual function.
7. No history of corneal trauma.
8. Subjects or their legal guardians voluntarily participate in this study, sign informed consent, good compliance and cooperation with follow-up visits.

Exclusion Criteria:

1. Lacrimal coating and blink function loss.
2. Schirmer's test result is less than 2mm for severe dry eye disease.
3. Pregnant and lactating women (pregnancy defined in this study as positive urine pregnancy test).
4. Currently is involved in clinical trials of other drugs or medical devices.
5. Active eye infection (including but not limited to: blepharitis, infectious conjunctivitis, keratitis, sclerotitis, endophthalmitis) in target eye or contralateral eye within 30 days prior to enrollment.
6. Ocular surface malignant tumor.
7. A history of allergic reaction or allergy to sodium luciferin, allergy to protein products used for treatment or diagnosis, allergy to ≥ 2 drugs or non-drug factors, or current allergic disease.
8. current in an infectious disease requiring oral, intramuscular or intravenous administration.
9. Patients with systemic immune diseases.
10. Any uncontrolled clinical problems (such as severe mental, neurological, cardiovascular, respiratory and other systemic diseases and malignant neoplasms).
11. Not effective contraception.
12. In uncontrolled hypertension, systolic is no less than 160 mmhg, diastolic is no less than 100 mmhg.
13. In uncontrolled diabetes, fasting glucose is no less than 10.0umol/L.
14. Renal insufficiency, serum creatinine is more than 133umol/L.
15. Arrhythmia, myocardial ischemia, myocardial infarction (diagnosed by electrocardiogram).
16. Liver dysfunction, al ANINE aminotransferase and aspartate aminotransferase levels are higher than 80 IU/L.
17. Platelet level is below 100,000 /uL or above 450,000 /uL.
18. Hemoglobin level is below 10.0g/dL (male) or 9.0g/dL (female).
19. No anticoagulant was used, prothrombin time is higher than 16s, and thrombin time of activated part is higher than 50s.
20. HIV infection (HIV-positive).
21. Subjects lack compliance with the study or the ability to sign informed consent.
22. There are currently signs of systemic infection, including fever and ongoing antibiotic treatment (in this study, systemic infection was defined as deviation from normal values of white blood cells, lymphocytes, and neutrophils on routine blood tests).
23. Administration of Glucocorticoids and other systemic immunosuppressive drugs.
24. The investigator judges other conditions unsuitable for the trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04560790
• Other Study ID Numbers: JYMS-CXL#02
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Shanghai BDgene Co., Ltd.
• Study Sponsor: Shanghai BDgene Co., Ltd.
• Collaborators: Eye & ENT Hospital of Fudan University

Investigators

• Principal Investigator: Yujia Cai, PhD; Shanghai BDgene Co., Ltd.

• PRS Account: Shanghai BDgene Co., Ltd.
• Verification Date: November 2020