Tailored Lighting and Melatonin for Sleep Disorders in Long COVID

Overseen By Barrie L Harper, BSMT (ASCP) PMP

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Duke University

Must not be taking: Sleep medications

Disqualifiers: Severe visual impairments, photosensitivity, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

600 Participants Needed

Trial Summary

What is the purpose of this trial?

The platform protocol is designed to be flexible so that it is suitable for a range of study settings and intervention types. Therefore, the platform protocol provides a general protocol structure that can be shared by multiple interventions and allows comparative analysis across the interventions. For example, objectives, measures, and endpoints are generalized in the platform protocol, but intervention-specific features are detailed in separate appendices. This platform protocol is a prospective, multi-center, multi-arm, randomized controlled platform trial evaluating potential interventions for PASC-mediated sleep disturbances. The hypothesis is that symptoms of sleep and circadian disorders that emerge in patients with PASC can be improved by phenotype-targeted interventions. Specific sleep and circadian disorders addressed in this protocol include sleep-related daytime impairment (referred to as hypersomnia) and complex PASC-related sleep disturbance (reflecting symptoms of insomnia and sleep-wake rhythm disturbance).

Will I have to stop taking my current medications?

If you are taking sleep medication, you will need to stop taking it for 4 weeks before starting the trial. For other medications, the protocol does not specify any requirements.

What data supports the effectiveness of the treatment Tailored Lighting and Melatonin for Sleep Disorders in Long COVID?

Research shows that melatonin can help regulate the body's internal clock and improve sleep patterns, especially in people with disrupted sleep-wake cycles. Light therapy, when used correctly, can also adjust circadian rhythms, making both treatments potentially beneficial for sleep disorders. ^{1 2 3 4 5}

Is melatonin and tailored lighting safe for humans?

Melatonin, including its prolonged-release forms, has been studied for various sleep disorders and is generally considered safe for human use, with some studies showing it can improve sleep and adjust circadian rhythms. Light therapy, when used appropriately, is also considered safe and can enhance alertness and performance. ^{3 6 7 8 9}

How is the treatment of tailored lighting and melatonin unique for sleep disorders in Long COVID?

This treatment is unique because it combines tailored lighting and melatonin to adjust the body's internal clock (circadian rhythms), which can help improve sleep. Unlike other treatments, it uses light exposure to enhance alertness and performance while melatonin helps induce sleepiness, making it a novel approach for managing sleep disorders in Long COVID. ^{2 3 10 11 12}

Research Team

Christina Barkauskas, MD

Principal Investigator

Duke Clinical Research Institute

Susan Redline, MD MPH

Principal Investigator

Brigham and Women's Hospital

Eligibility Criteria

This trial is for individuals experiencing sleep disorders after COVID-19, often referred to as Long COVID. Participants should meet the general criteria listed in a related document (NCTXXXXXXXXX). Specific details about who can join are not provided here.

Inclusion Criteria

I meet the main study's requirements for RECOVER-SLEEP.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Baseline assessments are conducted before randomization to intervention groups

1 week

Treatment

Participants receive tailored lighting and melatonin interventions for sleep disturbances

8 weeks

Weekly visits (in-person or virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Melatonin
• Tailored lighting (TL)

Trial Overview The study tests if tailored lighting or melatonin can improve sleep issues in post-COVID patients. It's a multi-center trial where participants are randomly assigned to receive either real treatments or placebos for comparison.

Participant Groups

Group I: Active TL + Oral Melatonin Active Control 2 Interventions

The Complex PASC-Related Sleep Disturbances (CPSD) Appendix B combines brief education and a tailored sleep timing prescription for CPSD (referred to as RESET-PASC) with therapies that modify circadian timing for participants who report poor sleep quality. The intervention therapies involve tailored lighting (TL) and melatonin. Participants will be randomly assigned to one of four groups: (a) active TL + oral melatonin, (b) active TL + placebo melatonin, (c) placebo TL + oral melatonin, and (d) placebo TL + placebo melatonin. All groups will receive RESET-PASC. The intervention duration will be 8 weeks.

Group II: Active TL + Placebo Melatonin Active Control 2 Interventions

The Complex PASC-Related Sleep Disturbances (CPSD) Appendix B combines brief education and a tailored sleep timing prescription for CPSD (referred to as RESET-PASC) with therapies that modify circadian timing for participants who report poor sleep quality. The intervention therapies involve tailored lighting (TL) and melatonin. Participants will be randomly assigned to one of four groups: (a) active TL + oral melatonin, (b) active TL + placebo melatonin, (c) placebo TL + oral melatonin, and (d) placebo TL + placebo melatonin. All groups will receive RESET-PASC. The intervention duration will be 8 weeks.

Group III: Placebo TL + Oral Melatonin Active Control 2 Interventions

The Complex PASC-Related Sleep Disturbances (CPSD) Appendix B combines brief education and a tailored sleep timing prescription for CPSD (referred to as RESET-PASC) with therapies that modify circadian timing for participants who report poor sleep quality. The intervention therapies involve tailored lighting (TL) and melatonin. Participants will be randomly assigned to one of four groups: (a) active TL + oral melatonin, (b) active TL + placebo melatonin, (c) placebo TL + oral melatonin, and (d) placebo TL + placebo melatonin. All groups will receive RESET-PASC. The intervention duration will be 8 weeks.

Group IV: Placebo TL + Placebo Melatonin Placebo Group 2 Interventions

The Complex PASC-Related Sleep Disturbances (CPSD) Appendix B combines brief education and a tailored sleep timing prescription for CPSD (referred to as RESET-PASC) with therapies that modify circadian timing for participants who report poor sleep quality. The intervention therapies involve tailored lighting (TL) and melatonin. Participants will be randomly assigned to one of four groups: (a) active TL + oral melatonin, (b) active TL + placebo melatonin, (c) placebo TL + oral melatonin, and (d) placebo TL + placebo melatonin. All groups will receive RESET-PASC. The intervention duration will be 8 weeks.

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?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Findings from Research

Melatonin (MLT) is a powerful chronobiotic that can effectively entrain the sleep-wake cycle, particularly in totally blind individuals, by acting on the master circadian clock in the brain.

MLT is not just a sleep hormone but a signal of darkness that influences various circadian rhythms, and its effects are mediated through two receptors (MT1 and MT2), highlighting the potential for developing targeted therapies for sleep and circadian disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin and the circadian system: Keys for health with a focus on sleep. Pevet, P., Challet, E., Felder-Schmittbuhl, MP.[2021]

Circadian timing significantly affects mental and physical health, and treatments like light therapy and melatonin can help realign misaligned circadian rhythms.

The review discusses various treatment options, including light exposure and melatonin receptor agonists, emphasizing the importance of patient characteristics and safety in choosing the appropriate intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Light and Melatonin and Other Melatonin Receptor Agonists on Human Circadian Physiology. Emens, JS., Burgess, HJ.[2018]

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]

Melatonin (MLT) and its receptor agonists, such as ramelteon and agomelatine, have been shown to effectively promote sleep and treat insomnia, although the improvements in sleep maintenance are considered moderate.

Agomelatine not only aids in sleep but also serves as a promising treatment for depression, offering efficacy with a favorable side effect profile, highlighting its potential as a dual-action therapeutic agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin receptor agonists: new options for insomnia and depression treatment. Spadoni, G., Bedini, A., Rivara, S., et al.[2021]

Melatonin treatment showed varying efficacy in two patients with non-24 hour sleep-wake syndrome, with one patient experiencing improved sleep onset but no change in sleep-wake rhythm, while the other successfully shifted to a delayed sleep phase pattern.

The effects of melatonin were not consistent over time; after a 4-month break, re-administration did not restore the improved sleep-wake rhythm in the second patient, indicating that while melatonin can be beneficial, its effects may be temporary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin treatment for rhythm disorder. Kato, M., Kajimura, N., Sekimoto, M., et al.[2015]

Tasimelteon is the first FDA-approved medication specifically for non-24-hour sleep-wake disorder, acting as an agonist for melatonin receptors MT1 and MT2 to help regulate sleep cycles.

The drug works by mimicking the natural hormone melatonin, which helps to realign the body's circadian rhythm when it is disrupted, particularly in individuals who do not receive typical light cues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tasimelteon: first global approval. Dhillon, S., Clarke, M.[2022]

In a study involving 8 healthy male volunteers, the high dose (5 mg) of the melatonin agonist LY 156735 significantly improved the speed of physiological readaptation to a 9-hour time shift, indicating its potential effectiveness for treating circadian rhythm disorders.

The high dose also helped reduce performance deterioration associated with shift lag, although subjective well-being measures did not show significant changes with either the high or low doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial. Nickelsen, T., Samel, A., Vejvoda, M., et al.[2019]

In a study of 13 totally blind subjects, prolonged-release melatonin (PRM) improved mean nightly sleep duration by 43 minutes compared to 16 minutes in the placebo group, suggesting it may help with sleep difficulties in this population.

PRM was well-tolerated with mild to moderate adverse events, and its beneficial effects on sleep persisted even after discontinuation, indicating potential for stabilizing the biological clock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial. Roth, T., Nir, T., Zisapel, N.[2022]

A daily dose of 0.5 mg melatonin effectively entrained the cortisol rhythms in most blind subjects with free-running circadian rhythms, with 7 out of 10 subjects showing positive changes during the treatment period.

Melatonin treatment not only improved sleep duration at night but also reduced daytime napping, suggesting its acute soporific effects may contribute to better sleep quality, especially when administered at the right circadian time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects. Hack, LM., Lockley, SW., Arendt, J., et al.[2022]

Low-dose melatonin treatment can effectively promote sleep onset and maintenance without altering sleep architecture, making it a useful option for individuals with insomnia or circadian rhythm disorders.

High doses of melatonin (over 0.3 mg) may lead to side effects and disrupt circadian rhythms, highlighting the importance of using physiologic doses and ensuring quality control in melatonin supplements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin, Circadian Rhythms, and Sleep. Zhdanova, IV., Tucci, V.[2020]

Melatonin significantly reduces the time it takes to fall asleep (by about 7 minutes) and increases total sleep time (by about 8 minutes) in patients with primary sleep disorders, based on a meta-analysis of 19 studies involving 1683 participants.

While the effects of melatonin on sleep quality are modest, it is considered a safer alternative to other insomnia medications due to its benign side-effect profile, making it a viable option for treating sleep issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis: melatonin for the treatment of primary sleep disorders. Ferracioli-Oda, E., Qawasmi, A., Bloch, MH.[2021]

A prototype personal light-treatment device using low brightness blue LEDs was effective in suppressing nocturnal melatonin levels in older adults, with a 60% suppression observed at a high light level after 90 minutes.

The study indicates that higher levels of blue light provide quicker and more sustained melatonin suppression compared to lower levels, suggesting this device could be a practical solution for improving sleep quality in those with circadian sleep disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A personal light-treatment device for improving sleep quality in the elderly: dynamics of nocturnal melatonin suppression at two exposure levels. Figueiro, MG., Bierman, A., Bullough, JD., et al.[2021]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Melatonin and the circadian system: Keys for health with a focus on sleep. [2021]

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

Effect of Light and Melatonin and Other Melatonin Receptor Agonists on Human Circadian Physiology. [2018]

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

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

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

Melatonin receptor agonists: new options for insomnia and depression treatment. [2021]

5. Australia pubmed.ncbi.nlm.nih.gov

Melatonin treatment for rhythm disorder. [2015]

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

Tasimelteon: first global approval. [2022]

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

Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial. [2019]

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

Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial. [2022]

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

The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects. [2022]

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

Melatonin, Circadian Rhythms, and Sleep. [2020]

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

Meta-analysis: melatonin for the treatment of primary sleep disorders. [2021]

12. England pubmed.ncbi.nlm.nih.gov

A personal light-treatment device for improving sleep quality in the elderly: dynamics of nocturnal melatonin suppression at two exposure levels. [2021]