Safety of Topical Insulin Drops for Open-angle Glaucoma

• ClinicalTrials.gov Identifier: NCT04118920
• Recruitment Status: Suspended
• First Posted: October 8, 2019
• Last Update Posted: August 20, 2021
• Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)
• Information provided by (Responsible Party): Centre hospitalier de l'Université de Montréal (CHUM)

Study Description

Brief Summary:

Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by a permanent loss of retinal ganglion cells (RGCs), a group of central nervous system (CNS) neurons that convey visual information from the retina to the brain via their long axons. Clinically, axonal damage in RGC results in a loss of visual field and may lead to blindness. Currently, reducing eye pressure remains the sole target of proven glaucoma therapies. However, many patients continue to lose vision even when standard interventions are implemented, accentuating the unmet need for novel therapies.

Dendrites are processes that determine how neurons receive and integrate information. Dendrite retraction and synapse breakdown are early signs of several neurodegenerative disorders. In mammals, CNS neurons have an extremely limited capacity to regenerate after injury. To date, the ability of mammalian neurons to regrow dendrites and reestablish functional synapses has been largely ignored.

Insufficient insulin signaling has been implicated in diseases characterized by dendritic pathology, notably Alzheimer's disease and glaucoma. A versatile hormone, insulin readily crosses the blood-brain-barrier and influences numerous brain processes. In a mouse model of optic nerve transection, our team showed that insulin administration after optic nerve injury promoted robust dendritic regrowth, RGCs survival and retinal responses rescue, providing the first evidence of successful dendrite regeneration in mammalian neurons. Our research validates insulin as a powerful medication to restore dendritic function in glaucoma, forming the basis for using insulin as glaucoma treatment in humans.

Currently, insulin is approved for diabetes. Adverse events of systemic insulin include hypoglycemia, hypokalemia, lipodystrophy, allergies, weight gain, peripheral edema and drug interactions. Experimental use of ocular topical insulin have been tested in small cohorts of healthy individuals and diabetic patients, reporting no significant adverse events. However, these protocols varied in insulin posology and adverse events were only touched upon briefly, indicating the necessity to better characterize the safety profile of such off-label use of insulin before its application as a neuroprotective and regenerative treatment for glaucoma.

In this study, the investigators hypothesize that topical ocular insulin (up to 500 U/ml) at once per day dosing is safe in patients with open angle glaucoma.

Condition or disease	Intervention/treatment	Phase
Glaucoma	Drug: Topic insulin (4 units); Drug: Topic insulin (20 units)	Phase 1

Detailed Description:

Glaucoma: a major health care challenge of the 21st century

Glaucoma is a leading cause of irreversible blindness worldwide and is expected to affect 76 million people by the year 2020. In glaucoma, there is a permanent loss of retinal ganglion cells (RGCs), the long-projecting central nervous system (CNS) neurons that convey visual information from the retina to the brain via their axons. Clinically, such changes translate into a progressive damage of visual field and sometimes result in a complete loss of vision. Currently, intraocular pressure (IOP) reduction remains the sole target of proven glaucoma therapies, consisting of a wide range of eye drops, systemic medications, laser procedures and incisional surgeries. However, many patients continue to lose vision even when these therapies are implemented, exemplifying the unmet need for novel therapies that sustain RGC survival and stimulate their regeneration.

Dendrite pathology: an early sign of neuronal damage in glaucoma Dendrites are specialized processes that determine how neurons receive and integrate information within neuronal circuits. Dendrite retraction and synapse disassembly are early signs of pathology in several psychiatric and neurodegenerative disorders. Dendritic pathology occurs prior to soma or axon loss and correlates with substantial functional deficits. In mammals, CNS neurons have a limited capacity to regenerate after injury. While a large number of studies have focused on axonal regeneration, the ability of mammalian neurons to regrow dendrites and reestablish functional synapses has been largely ignored. This is a critical issue because pathological disconnection from pre-synaptic targets leads to persistent functional impairment and accrued neuronal death, contributing to vision loss in glaucoma.

The role of insulin in dendrite regeneration Aberrant or insufficient insulin signaling, even in the absence of diabetes, has been associated with neurodegeneration in diseases characterized by dendritic pathology, notably Alzheimer's and Parkinson's disease, as well as glaucoma. Traditionally viewed solely as a peripherally acting hormone, insulin crosses the blood-brain-barrier readily and can influence a number of physiological brain processes including neuronal survival, neurotransmission, and cognitive performance. Using a model of optic nerve transection (axotomy), members of our team (Agostinone et al. Brain 2018) showed that insulin administered as eye drops or systemically after dendrites had retracted, promoted robust dendritic growth that restored arbor area and complexity. Remarkably, insulin rescued excitatory postsynaptic sites and light-triggered retinal responses while promoting robust cell survival. This study provides the first evidence of successful dendrite regeneration in mammalian neurons. Unpublished data (manuscript in preparation) from a mouse glaucoma model by our colleagues at the CHUM (Agostinone et al., in preparation) also showed that insulin stimulates similar dendrite regeneration after ocular hypertension damage. These results confirm that injured murine RGCs can effectively regenerate dendrites and validate insulin as a powerful strategy to restore dendritic morphology in glaucoma, providing the basis for need of further investigation of insulin use as glaucoma treatment in humans.

Currently, insulin is approved for subcutaneous or intravenous use as a treatment for diabetes mellitus. Adverse events of systemic insulin include hypoglycemia, hypokalemia,allergies, weight gain, peripheral edema and drug interactions. Experimental use of ocular topical insulin have been tested in small cohorts of healthy individuals and diabetic patients, reporting no significant adverse events. However, these protocols varied in insulin posology and adverse events were only mentioned briefly, if at all, in most of these studies, indicating the necessity of better characterizing the safety profile of such off-label use of insulin prior to implementing its use as neuroprotective and regenerative treatment for glaucoma.

Experimental nature of the medication / treatment:

Topical application of insulin with concentrations of 100 U/ml (Humulin R U-100, Eli Lilly Canada, St-Laurent, Quebec, Canada) and 500 U/ml (Entuzity, Eli Lilly Canada, St-Laurent, Quebec, Canada) once per day to eyes diagnosed with open angle glaucoma. Both products of insulin are approved by Health Canada for subcutaneous and intravenous use for the treatment of diabetes mellitus. The proposed route of administration and indication of insulin use in this current study are therefore of off-label nature, for which the investigators will request a non-objection letter from Health Canada.

Hypothesis of the study: Topical ocular insulin (up to 500 U/ml) at once per day dosing is safe in patients with open angle glaucoma.

Objectives: To document and to report any ocular and/or systemic adverse events associated with topical insulin eye drops.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Single-arm prospective open-label interventional study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety of Topical Insulin Eye Drops for the Treatment of Open-angle Glaucoma
• Estimated Study Start Date: January 2022
• Estimated Primary Completion Date: August 2022
• Estimated Study Completion Date: November 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Topical insulin; Patients will receive topical insulin eye drops.	Drug: Topic insulin (4 units); N=6: 100 U/ml; 4 units of insulin per application; 40 microliters per drop; Drug: Topic insulin (20 units); N=6: 500 U/ml; 20 units of insulin per application; 40 microliters per drop

Outcome Measures

Primary Outcome Measures :

1. Rate of hypoglycemia [ Time Frame: 1 year ]
   Monitor blood glucose levels in patients
2. Rate of hypokalemia [ Time Frame: 1 year ]
   Monitor serum potassium levels in patients
3. Rates of other reported adverse events [ Time Frame: 1 year ]
   Monitor any adverse event in patients

Secondary Outcome Measures :

1. Snellen chart visual acuity expressed in logMAR [ Time Frame: 1 year ]
   Monitor visual acuity in patients
2. Intraocular pressure (IOP) [ Time Frame: 1 year ]
   Monitor IOP in patients
3. Average RNFL and GCC thickness on SD-OCT [ Time Frame: 1 year ]
   Monitor RNFL and GCC thickness in patients
4. Mean deviation on visual field (VF) [ Time Frame: 1 year ]
   Monitor mean deviation on VF in patients
5. PERG P50 implicit time [ Time Frame: 1 year ]
   Monitor P50 implicit time
6. P50-N95 amplitude on PERG [ Time Frame: 1 year ]
   Monitor P50-N95 amplitude via PERG

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

* Please note that this study is only open to patients who are Quebec residents and who are already followed at the Centre Hospitalier de l'Université de Montréal (CHUM).

Inclusion Criteria:

• Age of 18 years or older
• Capable to provide informed consent
• Diagnosed of terminal open angle glaucoma (visual acuity ≤ 20/200 and / or visual field of 20 degrees or less)
• Only one eye per patient will be selected as the study eye - if both eyes meet the inclusion criteria, the eye with the worse acuity and /or visual field will be selected. The contralateral eye will be left untouched.

Exclusion Criteria:

• Younger than 18 years of age
• Pregnant or breastfeeding woman
• Presence of any ocular pathologies other than glaucoma that contributes to the severe vision loss (retinopathy / maculopathy, non-glaucomatous optic neuropathy, severe uveitis, keratopathy, etc.)
• Diagnosis of glucose intolerance, type 1 or 2 diabetes mellitus (HbA1C > 5.7%)
• Visual acuity of no light perception (NLP)
• Unable to provide informed consent
• Unable to complete the tests and follow-ups required by the study

Contacts and Locations

Locations

Canada, Quebec

Centre Hospitalier de l'Université de Montréal

Montréal, Quebec, Canada, H2X 3E4

Sponsors and Collaborators

Centre hospitalier de l'Université de Montréal (CHUM)

Investigators

• Principal Investigator: Qianqian Wang, MD, FRCSC; Département d'ophtalmologie, Centre hospitalier de l'Université de Montréal

More Information

Publications:

Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006 Mar;90(3):262-7.

Agostinone J, Di Polo A. Retinal ganglion cell dendrite pathology and synapse loss: Implications for glaucoma. Prog Brain Res. 2015;220:199-216. doi: 10.1016/bs.pbr.2015.04.012. Epub 2015 Jun 30. Review.

Canadian Ophthalmological Society Glaucoma Clinical Practice Guideline Expert Committee; Canadian Ophthalmological Society. Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of glaucoma in the adult eye. Can J Ophthalmol. 2009;44 Suppl 1:S7-93. doi: 10.3129/cjo44s1. English, French. Erratum in: Can J Ophthalmol. 2009 Aug;44(4):477.

Schwartz M, London A. Glaucoma as a neuropathy amenable to neuroprotection and immune manipulation. Prog Brain Res. 2008;173:375-84. doi: 10.1016/S0079-6123(08)01126-6.

Frankfort BJ, Khan AK, Tse DY, Chung I, Pang JJ, Yang Z, Gross RL, Wu SM. Elevated intraocular pressure causes inner retinal dysfunction before cell loss in a mouse model of experimental glaucoma. Invest Ophthalmol Vis Sci. 2013 Jan 28;54(1):762-70. doi: 10.1167/iovs.12-10581.

Pang JJ, Frankfort BJ, Gross RL, Wu SM. Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice. Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2593-8. doi: 10.1073/pnas.1419921112. Epub 2015 Feb 9.

Hilliard MA. Axonal degeneration and regeneration: a mechanistic tug-of-war. J Neurochem. 2009 Jan;108(1):23-32. doi: 10.1111/j.1471-4159.2008.05754.x. Epub 2008 Nov 15. Review.

Kleinridders A. Deciphering Brain Insulin Receptor and Insulin-Like Growth Factor 1 Receptor Signalling. J Neuroendocrinol. 2016 Nov;28(11). doi: 10.1111/jne.12433.

Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol. 2013 Feb;47(1):145-71. doi: 10.1007/s12035-012-8339-9. Epub 2012 Sep 7. Review.

Agostinone J, Alarcon-Martinez L, Gamlin C, Yu WQ, Wong ROL, Di Polo A. Insulin signalling promotes dendrite and synapse regeneration and restores circuit function after axonal injury. Brain. 2018 Jul 1;141(7):1963-1980. doi: 10.1093/brain/awy142.

Bartlett JD, Turner-Henson A, Atchison JA, Woolley TW, Pillion DJ. Insulin administration to the eyes of normoglycemic human volunteers. J Ocul Pharmacol. 1994 Winter;10(4):683-90.

Bartlett JD, Slusser TG, Turner-Henson A, Singh KP, Atchison JA, Pillion DJ. Toxicity of insulin administered chronically to human eye in vivo. J Ocul Pharmacol. 1994 Spring;10(1):101-7.

Wang AL, Weinlander E, Metcalf BM, Barney NP, Gamm DM, Nehls SM, Struck MC. Use of Topical Insulin to Treat Refractory Neurotrophic Corneal Ulcers. Cornea. 2017 Nov;36(11):1426-1428. doi: 10.1097/ICO.0000000000001297.

Fai S, Ahem A, Mustapha M, Mohd Noh UK, Bastion MC. Randomized Controlled Trial of Topical Insulin for Healing Corneal Epithelial Defects Induced During Vitreoretinal Surgery in Diabetics. Asia Pac J Ophthalmol (Phila). 2017 Sep-Oct;6(5):418-424. doi: 10.22608/APO.201780. Epub 2017 Aug 22.

Bastion ML, Ling KP. Topical insulin for healing of diabetic epithelial defects?: A retrospective review of corneal debridement during vitreoretinal surgery in Malaysian patients. Med J Malaysia. 2013 Jun;68(3):208-16. Review.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2012 Jan;35 Suppl 1:S64-71. doi: 10.2337/dc12-s064.

Leon AC, Davis LL, Kraemer HC. The role and interpretation of pilot studies in clinical research. J Psychiatr Res. 2011 May;45(5):626-9. doi: 10.1016/j.jpsychires.2010.10.008. Epub 2010 Oct 28.

SA J. Sample size of 12 per group rule of thumb for a pilot study. Pharmaceutical Statistics. 2005;4(4):287-91.

Information for the Physician: Humulin R Regular Insulin Human Injection, USP, (rDNA origin) 100 units per ml (U-100). In: Administration FaD, editor.: Lilly USA; 2011.

• Responsible Party: Centre hospitalier de l'Université de Montréal (CHUM)
• ClinicalTrials.gov Identifier: NCT04118920
• Other Study ID Numbers: CE19.154
• First Posted: October 8, 2019
• Last Update Posted: August 20, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Centre hospitalier de l'Université de Montréal (CHUM):

Topical insulin; Dendrite regeneration

Additional relevant MeSH terms:

Glaucoma; Glaucoma, Open-Angle; Ocular Hypertension; Eye Diseases; Insulin; Insulin, Globin Zinc; Hypoglycemic Agents; Physiological Effects of Drugs