Melatonin for Diabetic Retinopathy

Overseen By Sirimon Reutrakul

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Illinois at Chicago

Must be taking: Anti-diabetes

Must not be taking: Melatonin, Antidepressants, Antipsychotics, Sedatives

Disqualifiers: Stroke, Dementia, Cancer, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

36 Participants Needed

Trial Summary

What is the purpose of this trial?

This study explores the use of melatonin in patients with diabetic retinopathy

Will I have to stop taking my current medications?

The trial requires that you stop using melatonin, antidepressants, antipsychotics, and sedatives or hypnotics. If you are taking any of these, you would need to stop before participating.

What data supports the effectiveness of the drug melatonin for diabetic retinopathy?

Research suggests that melatonin, a hormone known for its anti-inflammatory properties, can protect retinal cells and reduce inflammation in diabetic retinopathy, potentially making it a useful treatment for this condition. ^{1 2 3 4 5}

Is melatonin safe for human use?

Melatonin, including its prolonged-release form (Circadin), has been shown to be well tolerated in humans, with mild side effects like nausea, dizziness, restlessness, and headache reported in a small number of cases. It has been used safely in various conditions, including sleep disorders and diabetes-related complications. ^{2 6 7 8 9}

How does the drug melatonin differ from other treatments for diabetic retinopathy?

Melatonin is unique in treating diabetic retinopathy because it targets abnormal melatonin regulation linked to sleep and circadian rhythm issues, which are associated with the condition. Unlike other treatments, it may help by improving melatonin levels, potentially reducing oxidative stress and inflammation, and downregulating harmful proteins like VEGF, which are involved in the progression of diabetic retinopathy. ^{1 2 4 5 10}

Eligibility Criteria

This trial is for people aged 40-65 with Type 2 diabetes and moderate diabetic retinopathy. Candidates must not have severe memory issues, major untreated diseases like cancer or heart failure, uncontrolled blood pressure or diabetes, recent severe hypoglycemia, certain eye conditions, or be using melatonin or specific psychiatric drugs.

Inclusion Criteria

I have moderate or worse diabetic eye disease.

I have type 2 diabetes or my A1C level is 6.5% or higher.

I am between 40 and 65 years old.

Exclusion Criteria

I have had a stroke or a mini-stroke before.

You use illegal drugs.

I am currently taking melatonin.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive melatonin or placebo for 8 weeks to assess sleep and circadian regulation

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Melatonin
• Placebo

Trial Overview The study tests if melatonin can help patients with diabetic retinopathy. Participants will either receive melatonin or a placebo (a substance with no active drug). The goal is to see if there's any improvement in their condition compared to those who don't take the real medication.

Participant Groups

Group I: Control Active Control 1 Intervention

Placebo

Group II: Melatonin Active Control 1 Intervention

Melatonin

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

Approved in European Union as Circadin for:

• Insomnia in adults aged 55 and over
• Sleep disorders in children with autism spectrum disorder

Approved in European Union as Slenyto for:

• Insomnia in children and adolescents aged 2-18 with autism spectrum disorder

Approved in United States as Melatonin for:

• Sleep disorders in children with autism spectrum disorder
• Insomnia in adults

Who Is Running the Clinical Trial?

University of Illinois at Chicago

Lead Sponsor

Trials

653

Recruited

1,574,000+

University of Chicago

Collaborator

Trials

1,086

Recruited

844,000+

Findings from Research

In a study of 26 patients with diabetic retinopathy (DR) and 14 control subjects, higher melatonin levels were found in the aqueous humor of patients with proliferative diabetic retinopathy (PDR), suggesting a potential link between melatonin and the severity of DR.

Plasma melatonin levels did not show significant differences between DR patients and controls, indicating that the increase in melatonin may be localized to the eye rather than systemic, which could have implications for understanding the mechanisms of DR progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased melatonin levels in aqueous humor of patients with proliferative retinopathy in type 2 diabetes mellitus. Aydin, E., Sahin, S.[2020]

Type 2 diabetes patients with diabetic retinopathy (DR) showed significantly lower levels of urinary melatonin (aMT6s) compared to non-diabetic controls, indicating a potential disruption in melatonin regulation associated with DR.

These patients also reported poorer sleep quality and greater variability in sleep duration, suggesting that low melatonin levels may contribute to sleep irregularities and weak circadian signaling in T2D patients with DR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleep variability, 6-sulfatoxymelatonin, and diabetic retinopathy. Sirisreetreerux, S., Sujirakul, T., Nimitphong, H., et al.[2021]

Melatonin has been shown to inhibit the activation of Müller cells and reduce inflammatory cytokine production in both in vitro and in vivo models of diabetic retinopathy (DR), suggesting its potential as a protective agent against this condition.

The protective effects of melatonin are mediated through the upregulation of a specific molecular pathway (the long noncoding RNA maternally expressed gene 3/miR-204/sirtuin 1 axis), indicating a novel mechanism of action that could be targeted for therapeutic strategies in DR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin inhibits Müller cell activation and pro-inflammatory cytokine production via upregulating the MEG3/miR-204/Sirt1 axis in experimental diabetic retinopathy. Tu, Y., Zhu, M., Wang, Z., et al.[2021]

In a study of 56 non-shift workers with type 2 diabetes, it was found that obstructive sleep apnea (OSA) and diabetic retinopathy are associated with lower levels of nocturnal melatonin secretion, which in turn negatively impacts glycemic control as measured by HbA1c levels.

The analysis indicated that the severity of OSA indirectly affects glycemic control through reduced melatonin secretion, suggesting that melatonin supplementation could potentially benefit type 2 diabetes patients suffering from OSA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Associations between nocturnal urinary 6-sulfatoxymelatonin, obstructive sleep apnea severity and glycemic control in type 2 diabetes. Reutrakul, S., Siwasaranond, N., Nimitphong, H., et al.[2022]

Patients with type 2 diabetes, especially those with proliferative diabetic retinopathy (PDR), have significantly lower nighttime melatonin levels compared to nondiabetic individuals, indicating a potential disruption in melatonin secretion related to diabetes complications.

The study suggests that altered melatonin secretion in diabetic patients, particularly those with PDR, may contribute to the progression of diabetic complications, highlighting the importance of monitoring melatonin levels in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alteration of melatonin secretion in patients with type 2 diabetes and proliferative diabetic retinopathy. Hikichi, T., Tateda, N., Miura, T.[2021]

In a postmarketing surveillance study of 653 patients aged 55 and older, prolonged-release melatonin (PRM) significantly improved sleep quality from an average score of 4.2 to 2.6 and morning alertness from 4.0 to 2.5 over three weeks of treatment.

PRM demonstrated a low incidence of rebound insomnia (3.2% early withdrawal, 2.0% late withdrawal) and was well tolerated, with minimal adverse effects, suggesting it is a safe and effective alternative to traditional hypnotics for managing insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin. Hajak, G., Lemme, K., Zisapel, N.[2021]

Melatonin, a hormone with antioxidative and anti-inflammatory properties, shows promise in managing diabetes and its complications, particularly in type 2 diabetes, by improving glucose homeostasis and addressing related issues like oxidative stress and inflammation.

Exogenous melatonin treatment has demonstrated beneficial effects in various studies involving cell lines, rodent models, and diabetic patients, but there are conflicting reports on its efficacy, indicating the need for further research to confirm its safety and effectiveness in diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diabetes mellitus and melatonin: Where are we? Patel, R., Parmar, N., Pramanik Palit, S., et al.[2022]

Melatonin can effectively phase-shift circadian rhythms and improve sleep in totally blind individuals with non-24 hour sleep/wake disorder, especially when administered at the right time relative to their circadian phase.

Light exposure, particularly short wavelength light, can suppress melatonin production and influence circadian rhythms, indicating that optimizing light's spectral composition may enhance its effectiveness in regulating sleep patterns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of light and melatonin to phase-shift human circadian rhythms. Skene, DJ.[2019]

This study found that plasma melatonin levels were significantly lower in patients with diabetic retinopathy (DR) compared to healthy controls, suggesting that melatonin may play a role in the development of DR.

Plasma melatonin concentration could serve as a potential diagnostic biomarker for DR, with a high accuracy (AUC = 0.893), indicating its usefulness in identifying individuals at risk for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma melatonin levels in patients with diabetic retinopathy secondary to type 2 diabetes. Wan, WC., Long, Y., Wan, WW., et al.[2021]

Melatonin-loaded polydopamine nanoparticles (MPDANPs) have been developed to improve the delivery and bioavailability of melatonin, which is crucial for treating diabetic retinopathy (DR) by downregulating harmful factors like VEGF.

In both in vitro and in vivo studies, MPDANPs demonstrated protective effects against diabetic insults by inhibiting VEGF, CASPASE3, and PKCδ, showcasing their potential as a therapeutic candidate for managing DR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Melatonin Delivery by a Size-Controlled Polydopamine Nanoformulation Attenuates Preclinical Diabetic Retinopathy. Sardoiwala, MN., Nagpal, S., Bhatt, B., et al.[2023]

References

1. China pubmed.ncbi.nlm.nih.gov

Increased melatonin levels in aqueous humor of patients with proliferative retinopathy in type 2 diabetes mellitus. [2020]

2. Germany pubmed.ncbi.nlm.nih.gov

Sleep variability, 6-sulfatoxymelatonin, and diabetic retinopathy. [2021]

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

Melatonin inhibits Müller cell activation and pro-inflammatory cytokine production via upregulating the MEG3/miR-204/Sirt1 axis in experimental diabetic retinopathy. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Associations between nocturnal urinary 6-sulfatoxymelatonin, obstructive sleep apnea severity and glycemic control in type 2 diabetes. [2022]

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

Alteration of melatonin secretion in patients with type 2 diabetes and proliferative diabetic retinopathy. [2021]

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

Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin. [2021]

7. France pubmed.ncbi.nlm.nih.gov

Diabetes mellitus and melatonin: Where are we? [2022]

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

Optimization of light and melatonin to phase-shift human circadian rhythms. [2019]

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

Plasma melatonin levels in patients with diabetic retinopathy secondary to type 2 diabetes. [2021]

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

Improved Melatonin Delivery by a Size-Controlled Polydopamine Nanoformulation Attenuates Preclinical Diabetic Retinopathy. [2023]