Back to resultsA Single Intravitreal Injection of rAAV2-ND4 for the Treatment of Leber's Hereditary Optic Neuropathy
Primary Purpose
Leber Hereditary Optic Neuropathy
Status
Active
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
rAAV2-ND4
Sponsored by
About this trial
This is an interventional treatment trial for Leber Hereditary Optic Neuropathy focused on measuring LHON,G11778A mutation, rAAV2-ND4，gene therapy
Eligibility Criteria
Inclusion Criteria:
- Patients carry the mitochondrial point mutation at 11778, which is consistent with the diagnostic criteria for LHON.
- No apparent eye sight improvement in LHON patients or any other treatment within the past year.
- Eyesight of both eyes is below 0.3.
- Patients signed written informed consent.
- Patients are between the ages of 10 and 65 years old and able to tolerate the gene therapy procedure which includes local anesthesia.
- Patients are willing to follow the doctor's instructions and to consult the doctor at prescribed times.
- Patient's physical examination results are all normal, including liver function, kidney function, routine blood test, routine urine test, complete immunological test, and humoral immune response.
Exclusion Criteria:
- Patients who are wearing a cardiac pacemaker, suffering from severe heart, lung or kidney function failure, various hemorrhagic diseases, acute infectious diseases, high fever, or convalescing after heart surgery or who are pregnant are excluded.
- Patients who are participating in other clinical studies are excluded.
- Patients who suffer from a diagnosed mental problem are excluded.
- Patients who suffer from chronic diseases such as diabetes and hypertension are excluded.
- Patients who show abnormal test results such as positive AAV2 humoral immune response (positive means that the AAV2 neutralizing antibody assay of patient was significant different when comparing free serum with 1:20 serum concentrations) and abnormal human T lymphocyte subsets CD3+, CD3+/CD4+ and CD3+/CD8+ prior to gene therapy surgery are excluded.
Sites / Locations
- Department of Ophthalmology，Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
rAAV2-ND4
Arm Description
A Single IVT Injection of recombinant Adeno-Associated Virus-NADH dehydrogenase, subunit 4 (complex I)（rAAV2-ND4)（0.05ml).The dose is 1 × 10^10 vg/0.05 mL for test groups.
Outcomes
Primary Outcome Measures
BCVA
The Best Corrected Visual Acuity
Computerized Visual Field
Secondary Outcome Measures
VEP
visual evoked potential
RNFL
retinal nerve fiber layer
Liver function in plasma
kidney function in plasma
Full Information
NCT ID
NCT03153293
First Posted
May 10, 2017
Last Updated
September 15, 2020
Sponsor
Huazhong University of Science and Technology
Collaborators
Taihe Hospital
1. Study Identification
Unique Protocol Identification Number
NCT03153293
Brief Title
A Single Intravitreal Injection of rAAV2-ND4 for the Treatment of Leber's Hereditary Optic Neuropathy
Official Title
A Single Intravitreal Injection of rAAV2-ND4 for the Treatment of Leber's Hereditary Optic Neuropathy
Study Type
Interventional
2. Study Status
Record Verification Date
September 2020
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 27, 2017 (Actual)
Primary Completion Date
January 15, 2020 (Actual)
Study Completion Date
January 15, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Huazhong University of Science and Technology
Collaborators
Taihe Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This study is meant to evaluate the safety and efficacy of rAAV2-ND4 treatment for Leber hereditary optic neuropathy with the G11778A mutation in mitochondrial DNA.
Detailed Description
Leber's Optic Hereditary Neuropathy (LHON) is a maternally inherited ocular disorder primarily associated with mutations in mitochondrial DNA. The disease is a common cause of blindness in both eyes of affected teenagers and young adults. There is currently no approved effective treatment for LHON.
In 2011, the first LHON gene therapy investigator-initiated study was conducted (registered in December 2010 with ClinicalTrials.gov Identifier NCT01267422) to explore the safety and efficacy of gene therapy for LHON. The gene therapy was a recombinant adeno-associated virus serotype 2 containing human mitochondrial ND4 (MT-ND4) gene (rAAV2-ND4). By 36 months of follow-up, six out of nine patients who received the rAAV2-ND4 intravitreal injection experienced clinically significant vision improvement and no adverse events were observed.
This is an open-label, single-arm, multi-center study to further evaluate the safety and efficacy of rAAV-ND4 in the treatment of LHON patients with G11778A mutation. All patients will be treated with a single intravitreal injection rAAV-ND4, with dose 1 × 10^10 vg/0.05 mL in one of the eyes.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leber Hereditary Optic Neuropathy
Keywords
LHON,G11778A mutation, rAAV2-ND4，gene therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
159 (Actual)
8. Arms, Groups, and Interventions
Arm Title
rAAV2-ND4
Arm Type
Experimental
Arm Description
A Single IVT Injection of recombinant Adeno-Associated Virus-NADH dehydrogenase, subunit 4 (complex I)（rAAV2-ND4)（0.05ml).The dose is 1 × 10^10 vg/0.05 mL for test groups.
Intervention Type
Drug
Intervention Name(s)
rAAV2-ND4
Intervention Description
a Single IVT Injection
Primary Outcome Measure Information:
Title
BCVA
Description
The Best Corrected Visual Acuity
Time Frame
Change from Baseline at 12 months .
Title
Computerized Visual Field
Time Frame
Change from Baseline at 12 months .
Secondary Outcome Measure Information:
Title
VEP
Description
visual evoked potential
Time Frame
Change from Baseline at 12 months .
Title
RNFL
Description
retinal nerve fiber layer
Time Frame
Change from Baseline at 12 months .
Title
Liver function in plasma
Time Frame
Change from Baseline at 12 months .
Title
kidney function in plasma
Time Frame
Change from Baseline at 12 months .
10. Eligibility
Sex
All
Minimum Age & Unit of Time
10 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients carry the mitochondrial point mutation at 11778, which is consistent with the diagnostic criteria for LHON.
No apparent eye sight improvement in LHON patients or any other treatment within the past year.
Eyesight of both eyes is below 0.3.
Patients signed written informed consent.
Patients are between the ages of 10 and 65 years old and able to tolerate the gene therapy procedure which includes local anesthesia.
Patients are willing to follow the doctor's instructions and to consult the doctor at prescribed times.
Patient's physical examination results are all normal, including liver function, kidney function, routine blood test, routine urine test, complete immunological test, and humoral immune response.
Exclusion Criteria:
Patients who are wearing a cardiac pacemaker, suffering from severe heart, lung or kidney function failure, various hemorrhagic diseases, acute infectious diseases, high fever, or convalescing after heart surgery or who are pregnant are excluded.
Patients who are participating in other clinical studies are excluded.
Patients who suffer from a diagnosed mental problem are excluded.
Patients who suffer from chronic diseases such as diabetes and hypertension are excluded.
Patients who show abnormal test results such as positive AAV2 humoral immune response (positive means that the AAV2 neutralizing antibody assay of patient was significant different when comparing free serum with 1:20 serum concentrations) and abnormal human T lymphocyte subsets CD3+, CD3+/CD4+ and CD3+/CD8+ prior to gene therapy surgery are excluded.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bin Li, PhD,MD
Organizational Affiliation
Deputy Director of Ophthalmology,Tongji Hospital
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Yong Zhang, PhD,MD
Organizational Affiliation
Director of Ophthalmology，Shiyan Taihe Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Ophthalmology，Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
City
Wuhan
State/Province
Hubei
ZIP/Postal Code
430030
Country
China
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
27426279
Citation
Yang S, Ma SQ, Wan X, He H, Pei H, Zhao MJ, Chen C, Wang DW, Dong XY, Yuan JJ, Li B. Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy. EBioMedicine. 2016 Aug;10:258-68. doi: 10.1016/j.ebiom.2016.07.002. Epub 2016 Jul 6.
Results Reference
result
PubMed Identifier
27749593
Citation
Yang S, Yang H, Ma SQ, Wang SS, He H, Zhao MJ, Li B. Evaluation of Leber's hereditary optic neuropathy patients prior to a gene therapy clinical trial. Medicine (Baltimore). 2016 Oct;95(40):e5110. doi: 10.1097/MD.0000000000005110.
Results Reference
result
PubMed Identifier
27386292
Citation
Ran R, Yang S, He H, Ma S, Chen Z, Li B. A retrospective analysis of characteristics of visual field damage in patients with Leber's hereditary optic neuropathy. Springerplus. 2016 Jun 23;5(1):843. doi: 10.1186/s40064-016-2540-7. eCollection 2016.
Results Reference
result
PubMed Identifier
26892229
Citation
Wan X, Pei H, Zhao MJ, Yang S, Hu WK, He H, Ma SQ, Zhang G, Dong XY, Chen C, Wang DW, Li B. Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy. Sci Rep. 2016 Feb 19;6:21587. doi: 10.1038/srep21587.
Results Reference
result
PubMed Identifier
25950380
Citation
Yang S, He H, Zhu Y, Wan X, Zhou LF, Wang J, Wang WF, Liu L, Li B. Chemical and material communication between the optic nerves in rats. Clin Exp Ophthalmol. 2015 Nov;43(8):742-8. doi: 10.1111/ceo.12547. Epub 2015 Jun 25.
Results Reference
result
PubMed Identifier
24396955
Citation
Pei H, Wan X, Hu W, Dong X, Li B. Construction and detection of a novel type of recombinant human rAAV2/2-ND4. Eye Sci. 2013 Jun;28(2):55-9.
Results Reference
result
PubMed Identifier
23063736
Citation
Cui G, Ding H, Xu Y, Li B, Wang DW. Applications of the method of high resolution melting analysis for diagnosis of Leber's disease and the three primary mutation spectrum of LHON in the Han Chinese population. Gene. 2013 Jan 1;512(1):108-12. doi: 10.1016/j.gene.2012.09.110. Epub 2012 Oct 9.
Results Reference
result
PubMed Identifier
22612072
Citation
Shi H, Gao J, Pei H, Liu R, Hu WK, Wan X, Li T, Li B. Adeno-associated virus-mediated gene delivery of the human ND4 complex I subunit in rabbit eyes. Clin Exp Ophthalmol. 2012 Dec;40(9):888-94. doi: 10.1111/j.1442-9071.2012.02815.x. Epub 2012 Jul 2.
Results Reference
result
PubMed Identifier
26606867
Citation
Feuer WJ, Schiffman JC, Davis JL, Porciatti V, Gonzalez P, Koilkonda RD, Yuan H, Lalwani A, Lam BL, Guy J. Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results. Ophthalmology. 2016 Mar;123(3):558-70. doi: 10.1016/j.ophtha.2015.10.025. Epub 2015 Nov 19.
Results Reference
result
PubMed Identifier
5063796
Citation
Erickson RP. Leber's optic atrophy, a possible example of maternal inheritance. Am J Hum Genet. 1972 May;24(3):348-9. No abstract available.
Results Reference
result
PubMed Identifier
3201231
Citation
Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ 2nd, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. 1988 Dec 9;242(4884):1427-30. doi: 10.1126/science.3201231.
Results Reference
result
PubMed Identifier
1674640
Citation
Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet. 1991 Jun;48(6):1147-53.
Results Reference
result
PubMed Identifier
1463007
Citation
Mackey D, Howell N. A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology. Am J Hum Genet. 1992 Dec;51(6):1218-28.
Results Reference
result
PubMed Identifier
18441370
Citation
Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2240-8. doi: 10.1056/NEJMoa0802315. Epub 2008 Apr 27.
Results Reference
result
PubMed Identifier
18441371
Citation
Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231-9. doi: 10.1056/NEJMoa0802268. Epub 2008 Apr 27.
Results Reference
result
PubMed Identifier
18774912
Citation
Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008 Oct;19(10):979-90. doi: 10.1089/hum.2008.107.
Results Reference
result
PubMed Identifier
22644094
Citation
Hufnagel RB, Ahmed ZM, Correa ZM, Sisk RA. Gene therapy for Leber congenital amaurosis: advances and future directions. Graefes Arch Clin Exp Ophthalmol. 2012 Aug;250(8):1117-28. doi: 10.1007/s00417-012-2028-2. Epub 2012 May 29.
Results Reference
result
PubMed Identifier
1928099
Citation
Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, Taylor L, Turnbull DM. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet. 1991 Nov;49(5):939-50.
Results Reference
result
PubMed Identifier
31237206
Citation
Zhang Y, Yuan JJ, Liu HL, Tian Z, Liu SW, Li B. Three Cases of Leber's Hereditary Optic Neuropathy with Rapid Increase in Visual Acuity After Gene Therapy. Curr Gene Ther. 2019;19(2):134-138. doi: 10.2174/1566523219666190618094505.
Results Reference
derived
Learn more about this trial
A Single Intravitreal Injection of rAAV2-ND4 for the Treatment of Leber's Hereditary Optic Neuropathy
We'll reach out to this number within 24 hrs