Sleep Treatments for Long COVID Syndrome

Recruiting at 50 trial locations

Overseen By Aric Prather

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Duke University

Disqualifiers: Pregnancy, Untreated sleep apnea, Narcolepsy, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 8-10 weeks

1074 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find effective treatments for sleep issues that have developed or worsened after a COVID-19 infection, known as Long COVID Syndrome. It will explore different interventions to improve sleep problems such as hypersomnia (excessive daytime sleepiness) and complex sleep disturbances, including insomnia and disrupted sleep-wake cycles. The trial includes various treatments like melatonin (a hormone that regulates sleep), tailored lighting (a therapy using specific light settings), and wake-promoting drugs. Individuals who have experienced new or worsening sleep problems for at least 12 weeks following a COVID-19 infection may be a good fit for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that modafinil is usually well-tolerated for treating sleep disorders. The FDA has approved it for conditions like narcolepsy that cause excessive daytime sleepiness. Some studies suggest it can help with fatigue and mental clarity, although it may not always outperform a placebo.

Solriamfetol is another drug that promotes wakefulness. It is also FDA-approved for similar sleep issues, and real-world safety reviews indicate it is generally safe, though some side effects have been reported.

Melatonin, commonly used to aid sleep, has been studied as a supportive treatment for COVID-19. Research suggests it can improve health conditions and speed up recovery when used with other treatments, indicating it is safe and effective for sleep problems.

Tailored lighting (TL) therapy is a newer method to help adjust sleep patterns. While there is less direct safety data, it is a non-invasive treatment, suggesting a low risk of side effects.

In this trial, participants will try these treatments for sleep issues related to Long COVID. Each treatment has a safety profile that supports its use in clinical settings. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these treatments for sleep disturbances in Long COVID because they offer a unique approach to managing symptoms that differ from the standard of care. The trial explores the use of tailored lighting (TL) and melatonin in a novel combination. Unlike traditional sleep aids, which primarily target sleep induction or maintenance, TL and melatonin aim to modify circadian rhythms, addressing underlying sleep-wake cycle disruptions. Additionally, the inclusion of wake-promoting drugs like modafinil or solriamfetol provides an alternative way to manage hypersomnia by enhancing alertness, offering potential benefits for those who don't respond well to conventional therapies. These innovative strategies could offer new hope for improving quality of life for those with complex post-COVID sleep issues.

What evidence suggests that this trial's treatments could be effective for PASC-mediated sleep disturbances?

This trial will explore various treatments for sleep disturbances associated with long COVID. In the Hypersomnia Arm, participants may receive modafinil or solriamfetol. Research suggests these drugs might help with tiredness and thinking problems by increasing alertness and reducing sleepiness. However, no specific studies have yet examined their use for long COVID.

In the Complex PASC-related Sleep Disturbances (CPSD) Arm, participants will be randomly assigned to receive combinations of tailored lighting (TL) and melatonin. Melatonin might improve sleep quality and help reset the body's internal clock, which long COVID can disrupt. Adjusting light exposure is another method to help reset sleep patterns for better rest. While data is limited, these treatments are based on known methods that might help with sleep issues in long COVID. ^{1 2 3 4 6}

Who Is on the Research Team?

Susan Redline, MD MPH

Principal Investigator

Brigham and Women's Hospital

Christina Barkauskas, MD

Principal Investigator

Duke Clinical Research Institute

Are You a Good Fit for This Trial?

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 case was suspected or probable before May 1, 2021.

My self-reported health score is 60 or higher.

I recently started having a fever and cough or at least three symptoms like sore throat or headache.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Melatonin
• Melatonin Placebo
• Tailored lighting (TL) Active

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.

How Is the Trial Designed?

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 (\> 55) 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 (≥55) 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.

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11363684/

Postacute Sequelae of COVID (PASC or Long COVID) There is a correlation between long COVID brain fog, muscle pain, and longer time to clear SARS-CoV-2 RNA from the upper respiratory tract during acute ...

2. academic.oup.com academic.oup.com/ofid/article/11/9/ofae462/7733485

Postacute Sequelae of COVID (PASC or Long COVID) Here, we share the evidence regarding the abnormalities associated with postacute sequelae of COVID-19 (PASC) and therapeutics.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06404086

NCT06404086 | RECOVER-SLEEP: Platform Protocol This is a double-blind, phase 2, randomized, placebo-controlled, interventional trial that combines brief education and a tailored sleep timing prescription for ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39236463/

Sleep disorder syndromes of post-acute sequelae of SARS ... Results: In 42 patients with PASC, five categories of sleep disorder syndromes were observed following a sleep clinic evaluation, including obstructive sleep ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06404112?cond=Post-Acute%20COVID19%20Syndrome&limit=100&aggFilters=status:rec&rank=75

RECOVER-SLEEP: Platform Protocol, Appendix_B (CPSD) The platform protocol is designed to be flexible so that it is suitable for a range of study settings and intervention types.

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1896112623000342

Safety and efficacy of melatonin as an adjuvant therapy in ... Melatonin was found to have substantial effects on COVID-19 patients when used as adjuvant therapy, enhancing clinical improvement and decreasing time to ...