Sleep Treatments for Long COVID Syndrome

Recruiting at 33 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Duke University

Disqualifiers: Pregnancy, Untreated sleep apnea, Narcolepsy, others

No Placebo Group

Prior Safety Data

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).

Do I need to stop taking my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that some medications might be prohibited, and you may need to stop them if they interfere with the study intervention. Please check the specific appendices for details or consult with the trial team.

What data supports the effectiveness of the drug Melatonin for treating sleep issues in Long COVID patients?

Research suggests that Melatonin, known for its sleep-regulating properties, may help with sleep disturbances in Long COVID due to its ability to reduce inflammation and oxidative stress, which are common in COVID-19. Additionally, Melatonin's role as an antioxidant and its potential to improve cognitive issues like 'brain fog' make it a promising option for managing Long COVID symptoms. ^{1 2 3 4 5}

Is melatonin safe for human use?

Melatonin, including its prolonged-release form (Circadin), has been shown to be generally safe for human use, with mild side effects like nausea, dizziness, restlessness, and headache reported in a small number of cases. It has been used successfully to improve sleep in various conditions without causing dependency or significant withdrawal symptoms. ^{5 6 7 8 9}

How does the drug melatonin differ from other treatments for long COVID syndrome?

Melatonin is unique for long COVID syndrome due to its potential to reduce symptoms like 'brain fog' and fatigue through its antioxidant, anti-inflammatory, and immune-modulating properties. Unlike other treatments, it may also help restore sleep patterns disrupted by COVID-19 and has a high safety profile, making it a promising option for managing long COVID symptoms. ^{1 2 3 4 10}

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 adults over 18 who've had COVID-19 and are now experiencing new or worsened sleep problems lasting at least 12 weeks. Participants must have been in contact with a COVID case, hospitalized with respiratory symptoms, or tested positive. They should be able to consent, complete surveys/assessments, follow up on visits, and use birth control if applicable.

Inclusion Criteria

My self-reported health score is 60 or higher.

I am 18 years old or older.

My case was suspected or probable before May 1, 2021.

Trial 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

1-2 weeks

Treatment

Participants receive phenotype-targeted interventions for sleep disturbances

8-10 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Melatonin (Hormone Therapy)
• Melatonin Placebo (Hormone Therapy)
• Tailored lighting (TL) Active (Other)

Trial Overview The RECOVER-SLEEP trial tests multiple treatments for post-COVID sleep issues: Melatonin, Modafinil, Solriamfetol and Tailored lighting (TL), each against a placebo. It's multi-center and randomized; patients don't choose their treatment.

Participant Groups

Group I: Hypersomnia Arm (Appendix A) Experimental Treatment 4 Interventions

This is a double-blind, phase 2, randomized, placebo-controlled interventional trial of a wake-promoting drug (modafinil or solriamfetol) to treat hypersomnia, defined by elevated scores (\> 60) on the PROMIS 8a SRI scale, in participants with PASC. Participants will be randomized to study drug or control. Participants who meet the eligibility criteria for modafinil will receive either active modafinil or modafinil-matched control. If modafinil is contraindicated, participants will be assessed for solriamfetol. If participants are eligible for solriamfetol, they will receive either active solriamfetol or solriamfetol-matched control. If solriamfetol is contraindicated, participants will be excluded from Appendix A. Modafinil and solriamfetol will be analyzed as a single wake-promoting drug condition versus control. The intervention duration will be 10 weeks. Anticipated enrollment is 474 participants. Details about the Hypersomnia Appendix are available under NCT06404099.

Group II: Complex PASC related Sleep Disturbances (CPSD) Arm (Appendix B ) Experimental Treatment 4 Interventions

This is a double-blind, phase 2, randomized, placebo-controlled, interventional trial that combines brief education and a tailored sleep timing prescription for CPSD with therapies that modify circadian timing for participants who report poor sleep quality or daytime sleep-related impairment, defined by elevated scores (≥60) on the PROMIS 8b SD scale, in participants with symptoms that occurred or worsened after COVID-19 infection. Interventions involve tailored lighting (TL) and melatonin. Participants will be randomly assigned to 1 of 4 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 BBT-CPSD. It is a 2x2 factorial design schema. The intervention duration will be 8 weeks. Anticipated enrollment for this appendix is 600 participants. Additional details about the CPSD Appendix are available under NCT06404112.

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Findings from Research

Melatonin may help alleviate long COVID symptoms such as cognitive issues, chronic fatigue, and muscle weakness due to its antioxidant, anti-inflammatory, and immuno-modulatory properties.

As a neuroprotective agent, melatonin could be beneficial in managing 'brain fog' and pain associated with long COVID, suggesting a need for further research on its therapeutic use in these neurological symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible Application of Melatonin in Long COVID. Cardinali, DP., Brown, GM., Pandi-Perumal, SR.[2022]

Approximately 40% of individuals infected with SARS-CoV-2 experience persistent symptoms, known as 'LONG COVID,' even after 12 weeks, indicating a need for effective treatments for these ongoing issues.

Melatonin, a hormone that activates the NRF2 transcription factor and may help reduce oxidative stress, is proposed as a potential treatment for LONG COVID symptoms like insomnia and fatigue, but further clinical trials are necessary to evaluate its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"LONG COVID"-A hypothesis for understanding the biological basis and pharmacological treatment strategy. Jarrott, B., Head, R., Pringle, KG., et al.[2022]

Melatonin, known for treating sleep disorders, shows promise as a treatment for sleep disturbances related to COVID-19 due to its safety profile and lack of adverse effects on respiratory function.

Preclinical data suggest that melatonin may inhibit the progression of COVID-19 by reducing inflammation, limiting tissue damage, and potentially enhancing the efficacy of COVID-19 vaccinations, although further clinical trials are necessary to confirm these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin as a Potential Adjuvant Treatment for COVID-19 beyond Sleep Disorders. Wichniak, A., Kania, A., Siemiński, M., et al.[2022]

Melatonin shows promise as a therapeutic agent against COVID-19 due to its antioxidant, anti-inflammatory, and immunomodulatory properties, potentially reducing the severity of the infection and its complications.

It may also enhance the effectiveness of anti-SARS-CoV-2 vaccines and help manage neurological issues related to COVID-19, making it a multifaceted treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can Melatonin Be a Potential "Silver Bullet" in Treating COVID-19 Patients? Cardinali, DP., Brown, GM., Pandi-Perumal, SR.[2023]

This clinical trial aims to evaluate the efficacy and safety of Melatonin in treating moderately ill COVID-19 patients, with 60 participants randomized into two groups to compare Melatonin with a placebo alongside standard treatment.

The primary outcomes include recovery rates of clinical symptoms and serum inflammatory markers, which will be assessed within seven days, providing insights into Melatonin's potential role in managing COVID-19 inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the efficacy and safety of Melatonin in moderately ill patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Ziaei, A., Davoodian, P., Dadvand, H., et al.[2022]

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]

Ramelteon and agomelatine are melatonergic agonists that effectively improve sleep quality and duration in patients with insomnia and major depressive disorder, respectively, by targeting MT1 and MT2 receptors in the brain.

A slow-release formulation of melatonin, Circadin, has been shown to be effective for treating sleep disorders in the elderly, highlighting the importance of formulation in enhancing therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic potential of melatonin agonists. Cardinali, DP., Pandi-Perumal, SR., Srinivasan, V., et al.[2019]

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]

Melatonin is a hormone that helps regulate sleep-wake cycles and has been used to treat various sleep disorders, including jet lag and insomnia.

Prolonged-release melatonin (Circadin) has recently been licensed in the UK specifically for treating primary insomnia, suggesting it may be an effective option for managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin for primary insomnia? [2017]

This clinical trial aims to evaluate the efficacy of melatonin as a preventive treatment for symptomatic SARS-CoV-2 infection among healthcare workers, with a total of 450 participants planned, and 312 already enrolled as of May 2020.

Participants will receive either melatonin or a placebo for 12 weeks, and the primary outcome will be the number of confirmed symptomatic COVID-19 infections, allowing for a thorough assessment of melatonin's potential protective effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial. García, IG., Rodriguez-Rubio, M., Mariblanca, AR., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Possible Application of Melatonin in Long COVID. [2022]

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

"LONG COVID"-A hypothesis for understanding the biological basis and pharmacological treatment strategy. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Melatonin as a Potential Adjuvant Treatment for COVID-19 beyond Sleep Disorders. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Can Melatonin Be a Potential "Silver Bullet" in Treating COVID-19 Patients? [2023]

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

Evaluation of the efficacy and safety of Melatonin in moderately ill patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. [2022]

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

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

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

Therapeutic potential of melatonin agonists. [2019]

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

Tasimelteon: first global approval. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Melatonin for primary insomnia? [2017]

10. England pubmed.ncbi.nlm.nih.gov

A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial. [2022]