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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04560790
Recruitment Status : Active, not recruiting
First Posted : September 23, 2020
Last Update Posted : May 26, 2021
Sponsor:
Collaborator:
Eye & ENT Hospital of Fudan University
Information provided by (Responsible Party):
Shanghai BDgene Co., Ltd.

Tracking Information
First Submitted Date  ICMJE September 17, 2020
First Posted Date  ICMJE September 23, 2020
Last Update Posted Date May 26, 2021
Actual Study Start Date  ICMJE November 4, 2020
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE Safety and Efficacy of CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy to Treat Refractory Viral Keratitis
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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  ICMJE
  • Viral Keratitis
  • Blindness Eye
  • Herpes Simplex Virus Infection
  • Cornea
Intervention  ICMJE Drug: BD111 Adult single group Dose
6 Participants will receive a single group dose administered via corneal injection in the study eye.
Study Arms  ICMJE 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: September 17, 2020)
6
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2022
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04560790
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Shanghai BDgene Co., Ltd.
Study Sponsor  ICMJE Shanghai BDgene Co., Ltd.
Collaborators  ICMJE Eye & ENT Hospital of Fudan University
Investigators  ICMJE
Principal Investigator: Yujia Cai, PhD Shanghai BDgene Co., Ltd.
PRS Account Shanghai BDgene Co., Ltd.
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP