Topical Insulin for Glaucoma

(TING1 Trial)

Overseen By Mariana Nunez, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Stanford University

Disqualifiers: Pregnancy, Diabetes, Retinopathy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 1-2 months

52 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing the safety of applying a special form of insulin directly to the eye in patients with optic nerve damage from conditions like glaucoma. The insulin may help heal and protect the damaged nerve cells. Insulin eyedrops have been shown to be feasible for lowering blood glucose in humans and have been tested for safety and efficacy in animal models.

Do I need to stop my current medications for this trial?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.

Is topical insulin safe for humans?

Research on various forms of insulin, including insulin lispro and insulin detemir, shows that they have a safety profile comparable to regular human insulin when used for diabetes. No significant differences in adverse events or complications were found, suggesting that these insulins are generally safe for human use. ^{1 2 3 4 5}

How is topical insulin unique as a treatment for glaucoma?

Topical insulin is unique because it is applied directly to the eye, unlike traditional glaucoma treatments that are often taken orally or as eye drops to reduce eye pressure. It has shown promise in healing corneal surface issues, which may offer additional benefits for eye health beyond just managing glaucoma. ^{6 7 8 9 10}

What data supports the effectiveness of the drug insulin for treating glaucoma?

Research shows that topical insulin has been effective in healing persistent corneal defects, which are injuries on the eye's surface. While this doesn't directly relate to glaucoma, it suggests insulin can help with certain eye conditions. ^{6 11 12 13 14}

Who Is on the Research Team?

Jeffrey L Goldberg, MD, PhD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for individuals with optic neuropathies like glaucoma, who can give informed consent and have one eye worse than the other; the worse eye will be treated. Excluded are those with diabetes, unreliable visual field tests, inability to consent or follow study procedures, pregnant or breastfeeding women, and severe vision loss from other ocular diseases.

Inclusion Criteria

I have been diagnosed with a type of optic nerve damage.

Only my worse eye will be treated in the study.

I am able to understand and agree to the study's procedures and risks.

Exclusion Criteria

I have severe vision loss due to an eye condition other than glaucoma.

I am unable to understand and agree to the study's details on my own.

I have been diagnosed with diabetes or glucose intolerance.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive topical sterile human recombinant insulin in various dosages for 5 days to 1 month

1-2 months

Daily visits for 5 days, then home administration for 1 month

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Insulin

Trial Overview The trial is testing the safety of topical sterile human recombinant insulin in two different doses (4 units and 20 units) on patients with glaucoma over a period of 1-2 months to see how well they tolerate it and any effects it has on their condition.

How Is the Trial Designed?

Group I: Low-Dose Insulin twice Daily Experimental Treatment 1 Intervention

Group 4. N=5. 1 drop of 100U/mL insulin administered twice daily for 5 days.

Group II: Low-Dose Insulin three times daily Experimental Treatment 1 Intervention

Group 6. N=5. 1 drop of 100U/mL insulin administered three times daily for 5 days.

Group III: Low dose topical insulin Experimental Treatment 1 Intervention

Group 1; N=6: 100 U/ml; 4 units of insulin per application, 1 drop done in clinic daily for 5 days

Group IV: Longer-term topical insulin Experimental Treatment 2 Interventions

Group 3 randomized; N=20: 10 subjects will receive the highest tolerated dose (e.g. from group 1 or group 2), 1 drop per day at home for 1 month, full testing pre- and post-treatment, and 10 subjects will receive 1/5 of the highest tolerated dose (either the lower dose, or if needed will dilute) 1 drop per day at home for 1 month, full testing pre- and post-treatment.

Group V: High-Dose Insulin twice Daily Experimental Treatment 1 Intervention

Group 5. N=5. 1 drop of 500U/mL insulin administered twice daily for 5 days.

Group VI: High-Dose Insulin three times daily Experimental Treatment 1 Intervention

Group 7. N=5. 1 drop of 500U/mL insulin administered three times daily for 5 days.

Group VII: High dose topical insulin Experimental Treatment 1 Intervention

Group 2; N=6: 500 U/ml; 20 units of insulin per application, 1 drop done in clinic daily for 5 days

Insulin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Insulin for:

• Diabetes mellitus

Approved in United States as Insulin for:

• Diabetes mellitus

Approved in Canada as Insulin for:

• Diabetes mellitus

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Published Research Related to This Trial

Liraglutide, a GLP-1 receptor agonist, effectively prevents retinal thickening in an animal model of type 2 diabetes, showing similar results to insulin and hydralazine when controlling blood glucose and blood pressure levels.

Despite preventing retinal thickening, liraglutide did not improve the proinflammatory state in the eyes of diabetic rats, indicating that while it has protective effects on retinal structure, it may not address underlying inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide-1 receptor agonist, liraglutide, attenuated retinal thickening in spontaneously diabetic Torii fatty rats. Inoue, K., Yamada, S., Hoshino, S., et al.[2023]

Topical insulin treatment has been found effective in healing persistent epithelial defects in the eye, with a total of 180 participants across nine studies showing complete resolution of symptoms.

The healing time varied from 2.5 to 60.9 days, with lower insulin concentrations leading to faster recovery, particularly in cases related to neurotrophic ulcers and complications from vitreoretinal surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of topical insulin for the treatment of surface corneal pathologies. Castro Mora, MP., Palacio Varona, J., Perez Riaño, B., et al.[2023]

In a study using an optic nerve crush rat model, treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide significantly reduced neuroinflammation markers, such as IL-1β and TNF-α, indicating its potential efficacy in treating neuroinflammation.

Lixisenatide also promoted retinal ganglion cell survival after acute optic nerve injury, suggesting it could be a promising new treatment for traumatic optic neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory effect of glucagon-like Peptide-1 receptor agonist on the neurosensory retina in an acute optic nerve injury rat model. Chung, YW., Lee, JY., Ju, HH., et al.[2022]

In a 5-year study involving 1,024 patients with type 2 diabetes, both insulin glargine and NPH insulin showed similar rates of progression in diabetic retinopathy, indicating that insulin glargine does not increase the risk of worsening eye conditions compared to NPH insulin.

While both treatments maintained comparable glycemic control, NPH insulin was associated with a higher incidence of severe hypoglycemia, suggesting that insulin glargine may be a safer option in terms of hypoglycemic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study. Rosenstock, J., Fonseca, V., McGill, JB., et al.[2022]

Lifitegrast ophthalmic solution 5.0% significantly improved inferior corneal staining scores (ICSS) in patients with mild-to-moderate dry eye disease (DED) in two out of three clinical trials, indicating its efficacy in treating this condition.

In participants with more severe symptoms, lifitegrast also demonstrated a significant reduction in eye dryness scores (EDS) in two studies, suggesting it may be particularly beneficial for those with moderate-to-severe DED.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials. Holland, EJ., Whitley, WO., Sall, K., et al.[2022]

A comparison of insulin lispro and regular human insulin (Humulin R) in 3634 patients with type 1 and type 2 diabetes showed no significant differences in treatment-emergent adverse events, indicating similar safety profiles for both insulins.

Both insulin therapies did not differ in their effects on the progression of chronic diabetes complications, such as retinopathy, neuropathy, cardiovascular disease, or kidney disease, suggesting that insulin lispro is as safe as Humulin R.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of insulin lispro: pooled data from clinical trials. Glazer, NB., Zalani, S., Anderson, JH., et al.[2019]

A comprehensive review of 50 studies over the past 20 years revealed significant differences in bioactivity between human insulin and various insulin analogues, affecting metabolism, cell growth, and other cellular functions.

The clinical implications of these differences in bioactivity are still unclear and require further investigation to understand their impact on different patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences in bioactivity between human insulin and insulin analogues approved for therapeutic use- compilation of reports from the past 20 years. Werner, H., Chantelau, EA.[2021]

In a 32-week study involving 686 patients with Type 2 diabetes, insulin detemir (IDet) therapy was found to be safe, with no serious adverse drug reactions reported and a significant reduction in total hypoglycemic events from 435 to 204.

Patients experienced improved glycemic control, as indicated by a decrease in glycated hemoglobin A1c from 9.9% to 7.7% and fasting plasma glucose from 11.9 mmol/L to 7.4 mmol/L, alongside a slight reduction in body weight.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical safety of insulin detemir in patients with Type 2 diabetes in the Gulf countries: The multicenter, noninterventional, open-label LevSafe study. El Shiekh, AR., Farrag, HA., Ashour, T., et al.[2020]

In a study involving 1008 patients, short-acting insulin lispro and regular insulin Humulin R showed similar effectiveness in controlling blood sugar levels and had comparable safety profiles, with no significant differences in hypoglycemia incidents.

After a year of continued lispro therapy, glycosylated hemoglobin (HbA1C) levels returned to baseline, indicating that while lispro was well tolerated in the short term, long-term efficacy may need further evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lispro insulin as premeal therapy in type 1 diabetes: comparison with Humulin R. Daniels, AR., Bruce, R., McGregor, L.[2022]

In two phase 3 studies involving 1012 participants (507 with type 1 diabetes and 505 with type 2 diabetes), SAR342434 (a biosimilar of insulin lispro) demonstrated a similar safety and efficacy profile compared to the original insulin lispro when used with insulin glargine.

Both treatments showed comparable rates of anti-insulin antibodies (AIA) development and no significant impact of AIA on glycemic control or safety outcomes, indicating that SAR342434 is a viable alternative to the original insulin lispro.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Insulin Antibodies and Adverse Events with Biosimilar Insulin Lispro Compared with Humalog Insulin Lispro in People with Diabetes. Home, P., Derwahl, KM., Ziemen, M., et al.[2022]

Topical insulin eye drops significantly increase insulin levels in the retina and optic nerve of both normal and diabetic rats, with peak levels occurring at 20 minutes for normal rats and 60 minutes for diabetic rats.

The accumulation of insulin in the retina is primarily due to the topical application rather than systemic absorption, as shown by experiments with decapitated rats and intravenous insulin injections that did not affect retinal insulin levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accumulation of topically applied porcine insulin in the retina and optic nerve in normal and diabetic rats. Koevary, SB., Nussey, J., Lake, S.[2011]

Topical insulin significantly improved the healing rate of corneal epithelial erosions in diabetic patients after vitreoretinal surgery, with treated eyes showing smaller defect sizes at multiple time points compared to those receiving conventional treatment.

In a case study of 15 eyes, diabetic patients treated with topical insulin re-epithelialized their corneal defects in 48 hours, while those treated conventionally took 72 hours, indicating that insulin may enhance healing in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical insulin for healing of diabetic epithelial defects?: A retrospective review of corneal debridement during vitreoretinal surgery in Malaysian patients. Bastion, ML., Ling, KP.[2018]

Topical insulin, when used alongside conventional treatment for recurrent epithelial corneal erosion, significantly improved healing times and reduced recurrence rates compared to conventional treatment alone, with results showing improvement at 2 weeks, 2 months, and 3 months.

The study demonstrated that topical insulin is well-tolerated, readily available, and cost-effective, making it a promising option for enhancing corneal regeneration in patients with recurrent epithelial erosions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of topical insulin for recurrent epithelial corneal erosions. Esmail, A., Ibrahim, M., Nage, S.[2023]

Insulin can be effectively absorbed into the bloodstream using an acidified Gelfoam ocular device without needing additional absorption enhancers, as demonstrated in a study with rabbits.

The study indicates that the use of 10% acetic acid alters the Gelfoam's properties, facilitating the efficient systemic absorption of insulin, which could have implications for non-invasive insulin delivery methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic absorption of insulin from a Gelfoam ocular device. Lee, Y., Yalkowsky, SH.[2019]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide-1 receptor agonist, liraglutide, attenuated retinal thickening in spontaneously diabetic Torii fatty rats. [2023]

2. Spain pubmed.ncbi.nlm.nih.gov

Effectiveness of topical insulin for the treatment of surface corneal pathologies. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Anti-inflammatory effect of glucagon-like Peptide-1 receptor agonist on the neurosensory retina in an acute optic nerve injury rat model. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Safety of insulin lispro: pooled data from clinical trials. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Differences in bioactivity between human insulin and insulin analogues approved for therapeutic use- compilation of reports from the past 20 years. [2021]

8. India pubmed.ncbi.nlm.nih.gov

Clinical safety of insulin detemir in patients with Type 2 diabetes in the Gulf countries: The multicenter, noninterventional, open-label LevSafe study. [2020]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Lispro insulin as premeal therapy in type 1 diabetes: comparison with Humulin R. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Anti-Insulin Antibodies and Adverse Events with Biosimilar Insulin Lispro Compared with Humalog Insulin Lispro in People with Diabetes. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Accumulation of topically applied porcine insulin in the retina and optic nerve in normal and diabetic rats. [2011]

12. Malaysia pubmed.ncbi.nlm.nih.gov

Topical insulin for healing of diabetic epithelial defects?: A retrospective review of corneal debridement during vitreoretinal surgery in Malaysian patients. [2018]

13. Ireland pubmed.ncbi.nlm.nih.gov

Efficacy of topical insulin for recurrent epithelial corneal erosions. [2023]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Systemic absorption of insulin from a Gelfoam ocular device. [2019]