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Leber's Hereditary Optic Neuropathy (LHON)Phase 2/3GOLDNCT04912843

Gene Therapy Clinical Trial for the Treatment Of Leber's HereDitary Optic Neuropathy

A Phase 2/3 study testing NR082 injection in people with Leber's Hereditary Optic Neuropathy (LHON), run by Wuhan Neurophth Biotechnology Limited Company at 1 site in China.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

The objective of this clinical study is to select the optimal dose and evaluate the safety and efficacy of NR082 in treatment of LHON caused by mitochondrial ND4 gene mutation. Part 1 (Phase 1/2) is a safety dose-finding study, which will enroll subjects aged ≥ 18 years old and ≤ 75 years old to receive a single… Read more about this study

Who is it for?
Ages 12 to 75 years
What is being tested?
NR082 injection
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
102 participants
Where
1 siteChina
Study dates
18 Jun 2021to 29 Feb 2028
Phase
Phase 2/3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 12 to 75 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Age at signing of informed consent form
  • In Part 1, the age of the subjects must be ≥ 18 years old and ≤ 75 years old
  • In Part 2, the age of the subjects must be ≥ 12 years old and ≤ 75 years old, and the 6 evaluable subjects must be monitored for at least 6 weeks during the safety run-in phase. If SRC believes that there is no safety issue, the randomized double-blind control study will be initiated Subject Type and Disease Characteristics
  • The clinical manifestation caused by LHON is vision loss, with a visual acuity of ≥ 0.5 LogMAR in BCVA in either eye
  • The genotype test result is that there is G11778A mutation in ND4 gene, and there are no other primary LHON-associated mutations in the mitochondrial DNA (mtDNA) (ND1[G3460A] or ND6[T14484C]) (confirmed by a CLIA-certified international laboratory)
  • The duration of vision loss in the eye with worse visual acuity lasted > 6 months and < 10 years at screening
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  • Pupils can be adequately dilated for a comprehensive eye examination and visual acuity test
  • Each eye of the subject must maintain the VA determined by manual visual acuity test (≤ 2.3 LogMAR) as defined in the ocular/vision examination manual (operating manual for optometry and VA examinations) in this study
  • Sign the written informed consent form and willing to comply with the clinical study protocol Sex
  • Male or female
  • Male subjects:
  • A male subject must agree to take contraceptive measures at least 6 months after the treatment visit, see Appendix 5 for details
  • Female subjects:
  • A female subject is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least one of the following conditions applies:
  • Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 or ii) A WOCBP who agrees to follow the contraception guidance in Appendix 5 for at least 6 months after the treatment visit Informed Consent
  • Written informed consent form must be obtained from the subject or his/her parent/legal guardian (if the subject is under 18 years of age) (Part 2) before any study-related procedures are performed (see Section 10.2) If the subject is legally identified as blind (>1.0 LogMARor decimal acuity meter reading < 0.1), an impartial witness must be present throughout the informed consent process and discussion process.

Who cannot join

  • Subjects who meet any of the following criteria will be excluded from the study:
  • Any known allergy and/or hypersensitivity to the study drug or its constituents
  • Contraindication to IVT injection in any eye
  • IVT drug delivery to any eye within 30 days prior to the screening visit
  • History of vitrectomy in either eye
  • Narrow anterior chamber angle in any eye contra-indicating pupillary dilation
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  • Presence of disorders or diseases of the eye or adnexa, excluding LHON, which may interfere with visual or ocular assessments, including spectral-domain optical coherence tomography (FD-OCT), during the study
  • Presence of known/documented mutations, other than the LHON-related mutation, which are known to cause pathology of the optic nerve, retina or afferent visual system
  • Presence of systemic or ocular/vision diseases, disorders or pathologies, other than LHON, known to cause or be associated with vision loss, or whose associated treatment(s) or therapy(ies) is/are known to cause or be associated with vision loss
  • Presence of optic neuropathy from any cause other than LHON
  • Presence of illness or disease that, in the opinion of the investigator, include symptoms and/or the associated treatments that can alter visual function, for instance cancers or pathology of the CNS, including multiple sclerosis (diagnosis of multiple sclerosis must be based on the 2010 Revisions to the McDonald Criteria) (Polman et al., 2011), and/or diseases or conditions that affect the safety of subjects participating in the study
  • History of recurrent uveitis (idiopathic or immune-related) or active ocular inflammation
  • Participated in another clinical study and receive IP within 90 days prior to the screening visit
  • Exceptions: Subjects who have completed the clinical study of idebenone as IP within 90 days prior to the screening visit, and has completely discontinued idebenone at least 7 days prior to dosing are still eligible to participate in the study.
  • Any eye has previously received ocular gene therapy
  • Subjects who refused to stop using idebenone
  • Have undergone ocular surgery of clinical relevance (per investigator's assessment) within 90 days prior to the screening visit
  • Female subjects who are breastfeeding or plan to breastfeed within the first 6 months after the administration of NR082 Injection
  • History of drug or alcohol abuse (including heavy smoking, i.e. > 20 cigarettes per day or > 20 pack-years [equivalent to one pack a day for 20 years or 2 packs a day for 10 years])
  • Subjects with positive human immunodeficiency virus (HIV), syphilis and HCV antibodies are excluded; subjects who have clinically significant active infection requiring treatment as shown by hepatitis B test (defined as positive hepatitis B core antibody [HBcAb] or hepatitis B surface antigen [HBsAg], hepatitis B virus deoxyribonucleic acid (HBV-DNA) >1,000 copies /mL or >lower limit of quantitative detection with the local laboratory method) will be excluded
  • Unable to tolerate or unable or unwilling to comply with all the protocol requirements
  • Subjects from the study site fail to comply with or do not agree to comply with local and institutional guidelines for suspected 2019 novel coronavirus (COVID-19) infection/testing
  • Any other exclusions determined by the investigator

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Xiaoning Guo, PHD contact

+86-21-64172955

info@neurophth.com

China1 site, 1 recruiting
  • Beijing Tongren Hospital, Capital Medical University

    Beijing

    Recruiting

Other trials in China

About this study

Official title: A Phase 1/2/3, Multi-center, Two-part Clinical Trial to Evaluate the Safety and Efficacy of Gene Therapy for Leber's Hereditary Optic Neuropathy (LHON) Associated With ND4 Mutation

The objective of this clinical study is to select the optimal dose and evaluate the safety and efficacy of NR082 in treatment of LHON caused by mitochondrial ND4 gene mutation. Part 1 (Phase 1/2) is a safety dose-finding study, which will enroll subjects aged ≥ 18 years old and ≤ 75 years old to receive a single unilateral intravitreal (IVT) injection of NR082 to observe its safety and efficacy. In Part 2 (Phase 3) of the clinical study, the dose recommended after the end of Part 1 is used to further verify the safety and efficacy of the study drug. Part 2 of the study is divided into the safety run-in phase and the randomized, double-blind and control study. Subjects aged ≥ 12 years and ≤ 75 years will be enrolled in the Part 2. The run-in phase will enroll 6 evaluable subjects. After monitoring for at least 6 weeks, if no new safety signals are observed, the clinical trial will enter the randomized, double-blind and control study phase upon approval by the Safety Review Committee(SRC). The clinical manifestation of all subjects is reduced visual acuity caused by LHON associated with ND4 mutation, and central laboratory test showed G11778A mutation (a CLIA-certified laboratory), while the reduced visual acuity lasted for > 6 months and < 10 years.

Read the detailed description

Part 1: Dose-Finding At the dose-finding part, the principle is that the Safety Review Committee (SRC) will determine whether to make dose adjustment based on the safety data of the starting dose in Part 1. The recommended dose (safe and effective dose) of the Part 2 study will be determined jointly by the SRC, IDMC, sponsor and the drug regulatory authority after the interim analysis in Part 1 is completed.

The starting dose in Part 1 is 1.5 × 109 vg, 0.05 mL eye/dose. The safety of the starting dose will be reviewed by the SRC and the dose escalation or de-escalation will be recommended by the SRC.

The safety of the starting dose will first be performed in 6 evaluable subjects.

Part 2 (including the safety run-in phase and the randomized, double-blind and sham-injection control study):

First Stage: safety run-in phase:

The safety run-in phase of Part 2 will enroll 6 evaluable subjects (including at least 1 minor subject aged ≥ 12 years and < 18 years) aged ≥ 12 years and ≤ 75 years at the dose determined in Part 1, namely 4.5 x 109 vg, 0.05 mL eye/dose (high dose) and monitor the safety for at least 6 weeks. If there is no new safety concern evaluated by the SRC, the randomized, double-blind, sham-injection control study can be initiated.

Second Stage: randomized, double-blind, sham-injection control study:

The randomized, double-blind, sham-injection control study of Part 2 is to verify the efficacy and safety of NR082 in LHON caused by mitochondrial gene ND4 mutation at the dose determined in Part 1 of the study, namely 4.5 x 109 vg, 0.05 mL eye/dose (high dose). This part is divided into the NR082 treatment group and the control group (sham-injection group).

Being tested
NR082 injection, Sham Injection
Medical subject headings
Optic Atrophy, Hereditary, Leber

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NR082 injectionDrug

    Intravitreal injection(IVT)

  • Sham InjectionDevice

    Sham Intravitreal Injection

Study groups in NCT04912843
Study groupRoleWhat they receive
NR082 injectionExperimental0.5E9 viral genomes (vg), 0.05 mL eye/dose ,single-dose,only one eye per subject; 1.5E9 viral genomes (vg), 0.05 mL eye/dose single-dose,only one eye per subject; 4.5E9 viral genomes (vg) , 0.05 mL eye/dose single-dose,only one eye per subject Part 1: Dose-Finding;The recommended dose (safe and effective dose) of the Part 2 study will be determined jointly by the SRC, IDMC, sponsor and the drug regulatory authority after the interim analysis in Part 1 is completed.
Receives: Drug: NR082 injection
sham-injectionSham comparatorPart2.Second Stage: randomized, double-blind, sham-injection control study One eye of each participant will undergo sham injection. Sham intravitreal injection will be performed by applying pressure to the eye at the location of a typical intravitreal injection procedure using the blunt end of a syringe without a needle.
Receives: Device: Sham Injection

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Safety and tolerability of NR082 at different doses

    Incidence rates of AEs, SAEs and DLTs within 12 weeks after injection of NR082 at different doses

    Measured: Part 1 (Phase1/2): 12 weeks

  2. Safety after NR082 treatment among subjects 12 ≤ aged ≤ 75 years

    Incidence rates of AEs and SAEs within 6 weeks after NR082 treatment

    Measured: Part 2 (Stage 1) : 6 weeks

  3. Efficacy of NR082 in study eye

    Proportion of ≥ 0.3 LogMAR from baseline in BCVA in the study eye in the NR082 treatment and the sham-injection at Week 52 after treatment

    Measured: Part 2 (Stage 2): 52 weeks

Secondary outcomes (6)
  1. The efficacy and safety following intravitreal injection of NR082 at different doses

    Improvent and mean change from baseline in BCVA; Change from baseline in visual field, contrast sensitivity and visual evoked potential

    Measured: Part 1 (Phase1/2), Part 2 (Stage 1 and Stage 2): Week 2, 6, 12, 26, 40 and 52

  2. Further assess the efficacy and safety following intravitreal injection of NR082 at different doses

    Descriptions of safety evaluation at Weeks 26, 40 and 52

    Measured: Part 1 (Phase1/2) and Part 2 (Stage 1): At Weeks 26, 40 and 52

  3. Immunogenicity and vector shedding/biodistribution

    Assessment of cell immunity, humoral immunity, vector DNA shedding in tears (both eyes) and biodistribution in whole blood

    Measured: Part 1 (Phase1/2), Part 2 (Stage 1 and Stage 2): Week 2, 6, 12, 26, 40 and 52

  4. The change in quality of life from baseline

    Change from baseline in VFQ-25 and SF-36

    Measured: Part 1 (Phase1/2), Part 2 (Stage 1 and Stage 2): Week 2, 26 and 52

  5. Morphological improvement after NR082 treatment

    Change from baseline in RNFL, GCL and IPL thickness in the study eye

    Measured: Part 1 (Phase1/2), Part 2 (Stage 1 and Stage 2): Week 2, 6, 12, 26, 40 and 52

  6. Safety and efficacy of NR082 caused by mitochondrial gene ND4 mutation

    Incidence rates of AEs and SAEs between the NR082 treatment group and the sham-injection group (ocular and non-ocular)

    Measured: Part 2 (Stage 2): Week 2, 6, 12, 26, 40 and 52

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Jun 2021
  2. Study start18 Jun 2021
  3. Primary completion29 Feb 2024 (estimated)
  4. Study completion29 Feb 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Sequential
Model description
Part 1: Dose-Finding At the dose-finding part, the principle is that the Safety Review Committee (SRC) will determine whether to make dose adjustment based on the safety data of the starting dose in Part 1. The recommended dose (safe and effective dose) of the Part 2 study will be determined jointly by the SRC, IDMC, sponsor and the drug regulatory authority after the interim analysis in Part 1 is completed. Part 2 : First Stage: safety run-in phase: The safety run-in phase of Part 2 will enroll 6 evaluable subjects (including at least 1 minor subject aged ≥ 12 years and \< 18 years) aged ≥ 12 years and ≤ 75 years at the dose determined in Part 1, namely 4.5 x 109 vg, 0.05 mL eye/dose (high dose) and monitor the safety for at least 6 weeks. If there is no new safety concern evaluated by the SRC, the randomized, double-blind, sham-injection control study can be initiated. Second Stage: randomized, double-blind, sham-injection control study.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
102 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04912843
Sponsor's protocol ID
NFS-01-101
Acronym
GOLD
Status last verified
Nov 2022
First submitted
13 May 2021
Last updated
14 Nov 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing NR082 injection in people with Leber's Hereditary Optic Neuropathy (LHON), run by Wuhan Neurophth Biotechnology Limited Company at 1 site in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 14 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Xiaoning Guo, PHD (+86-21-64172955, info@neurophth.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety and tolerability of NR082 at different doses (time frame: Part 1 (Phase1/2): 12 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Nov 2022.

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