Safety of Topical Insulin Drops for Open-angle Glaucoma

NCT04118920 | Active Not Recruiting Phase 1

• 1 other identifier: CE19.154
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

Conditions

Glaucoma

Keywords

Topical insulin; Dendrite regeneration

Outcome Measures

Primary Outcomes (4)

• Rate of hypoglycemia

  Monitor blood glucose levels in patients

  6 months

• Rate of hypokalemia

  Monitor serum potassium levels in patients

  6 months

• Rates of other reported adverse events

  Monitor any adverse event in patients

  6 months

• Ocular tolerability of the instilled drops

  Monitor the ocular tolerability of insulin drops on patients with a visual analog scale of ocular tolerability

  6 months

Secondary Outcomes (7)

• Snellen chart visual acuity expressed in logMAR

  6 months

• Intraocular pressure (IOP)

  6 months

• Average retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness on spectral domain optical coherence tomography (SD-OCT)

  6 months

• Perfusion density (PD) on optical coherence tomography-angiography (OCT-A)

  6 months

• Flow index (FI) on OCT-A

  6 months

Study Arms (2)

Topical insulin

EXPERIMENTAL

Patients will receive topical insulin eye drops.

Drug: Topical insulin (4 units); Drug: Topical insulin (20 units)

Topical artificial tears

SHAM COMPARATOR

Patients will receive topical artificial tears.

Drug: Artificial tears

Interventions

Topical insulin (4 units) DRUG

N=6: 100 U/ml; 4 units of insulin per application; 40 microliters per drop

Also known as: Humulin R (100 units/mL)

Topical insulin

Topical insulin (20 units) DRUG

N=6: 500 U/ml; 20 units of insulin per application; 40 microliters per drop

Also known as: Entuzity (500 units/mL)

Topical insulin

Artificial tears DRUG

N=3, 40 microliters per drop

Also known as: Refresh Plus Artificial Tears

Topical artificial tears

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-75 years
• Capable to provide informed consent
• Diagnosed of moderate primary open-angle glaucoma
• Moderate glaucoma is defined as:
• Vertical cup-to-disc ratio of 0.7-0.85 and (or)
• Moderate VF defect not within 10° of fixation (e.g. mean deviation (MD) from -6 to -12 dB on Humphrey Visual Field 24-2)

You may not qualify if:

• Normal serum potassium level (3.5-5.0mEq/L or 3.5-5.0 mMol/L) and HbA1C (≤5.7%) at baseline.
• Younger than 18 years of age or older than 75 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.)
• History of cataract surgery (complicated or uncomplicated) within 3 months of the study
• Any other intraocular surgery within 6 months of the initiation of the study
• Visual acuity of no light perception (NLP)
• Unable to provide informed consent
• Unable to complete the tests and follow-ups required by the study
• Diagnosis of glucose intolerance, type 1 or 2 diabetes mellitus (HbA1C \> 5.7%26)
• Diagnosis of conditions leading to baseline increased risk of hypokalemia and hypoglycemia such as:
• Chronic kidney disease (with or without dialysis)
• Cardiovascular disease, history of arrythmias
• Cirrhosis or other inflammatory liver diseases (hepatitis B and C)
• Inflammatory bowel disease

Sponsors & Collaborators

• Centre hospitalier de l'Université de Montréal (CHUM): lead

Study Sites (1)

Centre Hospitalier de l'Université de Montréal

Montreal, Quebec, H2X 3E4, Canada

Location

Related Publications (19)

• Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006 Mar;90(3):262-7. doi: 10.1136/bjo.2005.081224.

  PMID: 16488940 BACKGROUND

• 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.

  PMID: 26497792 BACKGROUND

• 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. No abstract available. English, French.

  PMID: 19492005 BACKGROUND

• 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.

  PMID: 18929122 BACKGROUND

• 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.

  PMID: 23221072 BACKGROUND

• 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.

  PMID: 25675503 BACKGROUND

• 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.

  PMID: 19054282 BACKGROUND

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

  PMID: 27631195 BACKGROUND

• 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.

  PMID: 22956272 BACKGROUND

• 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.

  PMID: 29931057 BACKGROUND

• 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. doi: 10.1089/jop.1994.10.683.

  PMID: 7714412 BACKGROUND

• 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. doi: 10.1089/jop.1994.10.101.

  PMID: 8207318 BACKGROUND

• 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.

  PMID: 28742619 BACKGROUND

• 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.

  PMID: 28828764 BACKGROUND

• 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.

  PMID: 23749008 BACKGROUND

• American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2012 Jan;35 Suppl 1(Suppl 1):S64-71. doi: 10.2337/dc12-s064. No abstract available.

  PMID: 22187472 BACKGROUND

• 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.

  PMID: 21035130 BACKGROUND

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

  BACKGROUND

• 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.

  BACKGROUND

MeSH Terms

Conditions

Glaucoma

Interventions

Insulin; Lubricant Eye Drops

Condition Hierarchy (Ancestors)

Ocular Hypertension; Eye Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Ophthalmic Solutions; Pharmaceutical Solutions; Solutions; Pharmaceutical Preparations; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Lubricants; Specialty Uses of Chemicals

Study Officials

• Qianqian Wang, MD, FRCSC

  Département d'ophtalmologie, Centre hospitalier de l'Université de Montréal

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single-arm prospective open-label interventional study

Study Record Dates

• First Submitted: October 2, 2019
• First Posted: October 8, 2019
• Study Start: March 27, 2023
• Primary Completion: August 20, 2024
• Study Completion: December 1, 2024
• Last Updated: August 21, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)