Metformin as a Neuroprotective Therapy for Glaucoma - A Randomized Controlled Trial

Sponsor
The University of Hong Kong (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05426044
Collaborator
(none)
240
2
42

Study Details

Study Description

Brief Summary

Glaucoma, a chronic degenerative disease of the optic nerve, is the leading cause of irreversible blindness worldwide. Although lowering the intraocular pressure (IOP) has been shown to be effective to slow optic nerve degeneration, a significant portion of glaucoma patients continue to develop progressive loss in vision despite adequate control of IOP. Development of neuroprotective therapy to prevent optic nerve degeneration by mechanisms other than IOP- lowering is critical to reduce the burden of glaucoma blindness. With 76 million glaucoma patients in 2020 worldwide, the need to investigate neuroprotection for glaucoma is pressing.

While metformin is a widely adopted oral hypoglycemic medication for treatment of type 2 diabetes mellitus (DM), increasing evidence from clinical studies has shown that metformin can decrease the risk of many age-related diseases including neurodegenerative diseases. In a retrospective study of 150,016 patients with DM, those taking metformin at >1500mg/day had a 25% reduced risk of development of open-angle glaucoma than those who took no metformin. Metformin has a high safety profile. We aim to investigate whether metformin can be repurposed to a neuroprotective therapy for glaucoma patients in a randomized controlled trial.

We propose to conduct a 24-month, double-blind, placebo-controlled, parallel group, multi- center trial, randomizing 240 primary open angle glaucoma patients who have progressive retinal nerve fiber layer ganglion cell inner plexiform layer (RNFL-GCIPL) thinning in at least one eye, as determined by wide-field optical coherence tomography Trend-based Progression Analysis, to receive metformin 1500mg/day or placebo. All patients will be followed up at 2- month intervals for IOP, RNFL-GCIPL thickness, and visual field (VF) measurements. The objectives are to compare (1) the rates of change of average RNFL-GCIPL thickness (primary outcome measure), and (2) the rates of change of VF mean deviation (MD) (secondary outcome measure) between treatment groups. We hypothesize that patients treated with metformin have a slower rate of RNFL-GCIPL thinning, and a slower rate of VF MD decline compared with those treated with placebo at similar levels of IOP over the 24-month follow-up.

The proposed study has the potential to mark a paradigm shift in the management of glaucoma patients by demonstrating that neuroprotection is attainable with metformin, which will alleviate the increasing burden of glaucoma blindness in China and other Asian countries where glaucoma patients with normal levels of IOP are prevalent. Furthermore, it will inform and impact the study design in future neuroprotection trials which can expedite the development of neuroprotective therapy for glaucoma.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Anticipated Enrollment :
240 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Single (Participant)
Primary Purpose:
Other
Official Title:
Metformin as a Neuroprotective Therapy for Glaucoma - A Randomized Controlled Trial
Anticipated Study Start Date :
Jul 1, 2022
Anticipated Primary Completion Date :
Dec 31, 2024
Anticipated Study Completion Date :
Dec 31, 2025

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Patients will receive oral metformin

twice daily, oral metformin 750mg (i.e. 1500mg/day)

Drug: Metformin
To investigate whether metformin has a neuroprotective effect in patients with primary open-angle glaucoma by comparing the rates of change of average retinal nerve fiber layer ganglion cell inner plexiform layer (RNFL-GCIPL) thickness (primary outcome measure) between patients randomized to receive metformin versus those randomized to receive placebo. To identify the risk factors associated with progressive RNFL-GCIPL thinning and progressive decline in visual field mean deviation in patients with glaucoma.

Device: Placebo
This study takes 24 months. Participants will have 12 visits within 24 months. All of the investigations will be carried out at Grantham Hospital and Hong Kong Eye Hospital. Patients will be randomly assigned in a 1:1 ratio to receive, twice daily, oral metformin 750mg (i.e. 1500mg/day) or identical-appearing oral placebo. The investigators and patients will be blinded to the treatment assignment. Participants will be followed up at 2-month intervals for 24 months.

Experimental: Patients will receive oral placebo.

twice daily, oral metformin 750mg (i.e. 1500mg/day)

Drug: Metformin
To investigate whether metformin has a neuroprotective effect in patients with primary open-angle glaucoma by comparing the rates of change of average retinal nerve fiber layer ganglion cell inner plexiform layer (RNFL-GCIPL) thickness (primary outcome measure) between patients randomized to receive metformin versus those randomized to receive placebo. To identify the risk factors associated with progressive RNFL-GCIPL thinning and progressive decline in visual field mean deviation in patients with glaucoma.

Device: Placebo
This study takes 24 months. Participants will have 12 visits within 24 months. All of the investigations will be carried out at Grantham Hospital and Hong Kong Eye Hospital. Patients will be randomly assigned in a 1:1 ratio to receive, twice daily, oral metformin 750mg (i.e. 1500mg/day) or identical-appearing oral placebo. The investigators and patients will be blinded to the treatment assignment. Participants will be followed up at 2-month intervals for 24 months.

Outcome Measures

Primary Outcome Measures

  1. Rates of RNFL-GCIPL thinning [24 months]

    The rates of RNFL-GCIPL thinning between the metformin-treated group and the placebotreated group will be compared using a linear mixed model after adjusting for clustering between fellow eyes and covariates (i.e.signal strength, baseline RNFL-GCIPL thickness, IOP during follow-up, age, and axial length).The average RNFL-GCIPL thickness of an eye in each visit (i.e. the dependent variable in the linear mixed model) is obtained from taking the

Secondary Outcome Measures

  1. Rates of change of VF MD [24 months]

    The rates of change of VF MD will be compared between treatment groups with linear mixed models as described; differences in time from baseline to the event of progressive RNFLGCIPL thinning (by TPA) and VF progression (by EMGT criteria) between treatment groups will be compared with Cox proportional hazards models using shared-frailty to adjust for correlation between fellow eyes. Missing data (e.g. lost to follow-up) will be imputed using multiple imputation by chained equations.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
Inclusion Criteria:

age ≥18 years; best corrected VA ≥20/40; IOP ≤24mmHg at the screening and baseline visits; and progressive RNFL-GCIPL thinning by TPA over the past 3 years in at least one eye (described in lines 202-215).

Exclusion Criteria:

patients with DM, kidney or liver diseases, pathological myopia, cognitive impairment (e.g. Alzheimer's disease), or diseases that may cause visual field loss or optic disc abnormalities other 169 than glaucoma; inability to perform reliable visual field; and suboptimal quality of OCT images (described in lines 198-200). Both eyes of a patient will be included in the analysis if both eyes are eligible for inclusion.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

  • The University of Hong Kong

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Prof Leung Kai Shun, Christopher, Chairperson and Clinical Professor, The University of Hong Kong
ClinicalTrials.gov Identifier:
NCT05426044
Other Study ID Numbers:
  • UW 21-586
First Posted:
Jun 21, 2022
Last Update Posted:
Jun 21, 2022
Last Verified:
Jun 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
Yes
Product Manufactured in and Exported from the U.S.:
Yes
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jun 21, 2022