RECOVER-SLEEP: Platform Protocol

RECOVER-SLEEP: A Platform Protocol for Evaluation of Interventions for Sleep Disturbances in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)

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).

Study Overview

• Status: Completed
• Conditions: Sleep Disturbance; Long COVID; Long COVID-19; Hypersomnia
• Intervention / Treatment: Drug: Melatonin; Device: Tailored lighting (TL) Active; Drug: Melantonin Placebo; Device: Tailored lighting (TL) Placebo; Drug: Modafinil; Drug: Modafinil Placebo; Drug: Solriamfetol; Drug: Solriamfetol Placebo

Detailed Description

Interventions will be added to the platform protocol as appendices. Each appendix will leverage all elements of the platform protocol, with additional elements described in the individual appendix.

After completing Baseline assessments, participants will be randomized to an intervention group, which is based on their sleep phenotype, or into a placebo/control group.

• Study Type: Interventional
• Enrollment (Actual): 830
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner University Medical Center Phoenix
    • Tucson, Arizona, United States, 85719
      • University of Arizona Banner Medical Center
    • Tucson, Arizona, United States, 85723
      • The Southern Arizona VA Health Care System
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
    • San Francisco, California, United States, 94143
      • University of California San Francisco General Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus
    • Denver, Colorado, United States, 80204
      • Denver Health and Hospital Authority
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20060
      • Howard University Hospital
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine Jacksonville
    • Lakeland, Florida, United States, 33805
      • Lakeland Regional Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Atlanta, Georgia, United States, 30310
      • Morehouse School of Medicine
    • Decatur, Georgia, United States, 30030
      • Atlanta VA Medical Center
    • Decatur, Georgia, United States, 30030
      • Emory Hope Clinic
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
    • Chicago, Illinois, United States, 60612
      • Cook County Health Specialty Care Center
    • Evanston, Illinois, United States, 60201
      • Northshore Medical Group
    • Peoria, Illinois, United States, 61606
      • Saint Francis Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University Of Kentucky
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Bayview Medical Center
    • Silver Spring, Maryland, United States, 20904
      • Jadestone Clinical Research, LLC
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Womens Hospital
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Med. Ctr.
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers University - Robert Wood Johnson Medical School
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • University of New Mexico
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
  • Ohio
    • Cincinnati, Ohio, United States, 45220
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Texas
    • Dallas, Texas, United States, 75235
      • Southwest Family Medicine Associates
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
    • Houston, Texas, United States, 77082
      • New Dawn Wellness and Medical Research Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
  • Washington
    • Kirkland, Washington, United States, 98034
      • Evergreen Hospital Medical Center
  • West Virginia
    • Huntington, West Virginia, United States, 25701
      • University Physicians and Surgeons (DBA Marshall Health)
    • Morgantown, West Virginia, United States, 26506
      • West Virginia Clinical and Translational Science Institute
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. ≥ 18 years of age at the time of enrollment

2. Previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization:

   Suspected* case of SARS-CoV-2 infection - Three options, A through C:

   A. Met the clinical OR epidemiological criteria:

   1. Clinical criteria: Acute onset of fever AND cough (influenza-like illness) OR Acute onset of ANY THREE OR MORE of the following signs or symptoms: fever, cough, general, weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, nausea, diarrhea, anorexia;
   2. Epidemiological criteria: Contact of a probable or confirmed case or linked to a COVID-19 cluster; or B. Presented with acute respiratory infection with a history of fever or measured fever of ≥ 38°C and cough, with onset within the last 10 days, and required hospitalization; or C. Presented with no clinical signs or symptoms, NOR meeting epidemiologic criteria with a positive professional use or self-test SARS-CoV-2 Antigen-Rapid Diagnostic Test.

   Probable* case of SARS-CoV-2 infection, defined as having met the clinical criteria above AND was a contact of a probable or confirmed case or is linked to a COVID-19 cluster; or

   Confirmed case of SARS-CoV-2 infection - Two options, A through B:

   A. Presented with a positive nucleic acid amplification test, regardless of clinical criteria OR epidemiological criteria; or B. Met clinical criteria AND/OR epidemiological criteria (See suspected case A), with a positive professional use or self-test SARS-CoV-2 Antigen-Rapid Diagnostic Test.

   * Suspected and probable cases will only be allowed if they occurred before May 1, 2021, and will be limited to 10% of the study population. Otherwise, confirmed cases are required.

3. New/worse sleep problems following a SARS-CoV-2 infection that have persisted for at least 12 weeks and are still present at the time of consent

4. PROMIS 8a SRI or 8b SD T Score ≥ 55**

   ** Screening with both the PROMIS 8a SRI and 8b SD will occur for the phenotype assessment portion of the protocol.

5. Willing and able to provide informed consent, complete the surveys and clinical assessments, and return for all of the necessary follow-up visits
6. Adequate method of birth control for participants of child-bearing potential

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Known active acute SARS-CoV-2 infection ≤ 4 weeks from consent
2. Known pregnancy, breastfeeding, or contemplating pregnancy during the study period
3. Untreated sleep apnea (AHI ≥ 15 or severe sleep-related hypoxemia)
4. Current night or rotating shift work
5. Known history of narcolepsy prior to SARS-CoV-2 infection
6. Any non-marijuana illicit drug use within 30 days of informed consent
7. Known history of severe mental disorder, such as psychotic disorders and bipolar disorder
8. Current or recent use (within the last 14 days) of study intervention or similar intervention to treat the underlying condition, unless a washout period is permitted per appendix*
9. Known allergy/sensitivity or any hypersensitivity to components of the study intervention or control*
10. Known contraindication(s) to study intervention including prohibited concomitant medications and without the ability to safely hold prohibited concomitant medications (see appendices)*
11. Currently receiving/using intervention from another clinical trial that could impact or mask treatment effect; refer to MOP for details
12. Any condition that would make the participant, in the opinion of the investigator, unsuitable for the study

(*)If only one study intervention appendix is open at the time of enrollment. If multiple study intervention appendices are open, a participant may be excluded from any study intervention appendix based on contraindications listed in the study intervention appendix, current use of study intervention, or known allergy/sensitivity/hypersensitivity yet remain eligible for the remaining study intervention appendices.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Hypersomnia Arm (Appendix A); 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.	Drug: Modafinil; Modafinil is used off-label based on supporting published evidence in major depressive disorder (antidepressant augmentation), multiple sclerosis-related fatigue, Parkinson disease-related excessive daytime sleepiness, and severe cancer-related fatigue (in patients receiving active treatment). Doses up to 400 mg/day, given as a singleMode dose, have been well tolerated, but there is no consistent evidence that this dose confers additional benefit beyond that of the 200 mg dose. Study drug administration will total 10 weeks.; Drug: Modafinil Placebo; The placebo will be tooled to look similar to the modafinil tablet, but it will not contain the active ingredient. Modafinil placebo dosing will follow the same titration scheme as modafinil treatment. Unblinded study personnel will manage modafinil and placebo disbursement to maintain blinding among participants and blinded study personnel, including site investigators.; Drug: Solriamfetol; The proposed doses and the schedule of dose escalation are consistent with currently approved FDA labeling for solriamfetol for other disorders of excessive daytime sleepiness. Solriamfetol dosing will total 10 weeks, including 3 weeks for titration and 7 weeks of maintenance. Solriamfetol will be given as a 75 mg tablet (1 or 2 per day) in the morning. The 3-week titration will be facilitated by phone calls between the study team and participants. Titrations in dose will be dependent upon participants' symptoms and tolerance to solriamfetol, with a goal of participants taking the highest dose permitted by symptoms. This dose will be used for the maintenance phase.; Drug: Solriamfetol Placebo; The placebo tablet will be tooled to look similar to the solriamfetol tablet, but it will not contain the active ingredient. Solriamfetol placebo dosing will follow the solriamfetol dosing scheme and goal. Unblinded study personnel will manage solriamfetol and placebo disbursement to maintain blinding among participants and blinded study personnel, including site investigators.
Other: Complex PASC related Sleep Disturbances (CPSD) Arm (Appendix B ); 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.	Drug: Melatonin; Melatonin dosing will be one tablet of 3 mg immediate release daily consumed 2 hours before the participant's desired bedtime, which is defined as the time at which the participant tries to fall asleep.; Device: Tailored lighting (TL) Active; TL will be delivered similarly to both active and placebo groups, but the circadian stimulus (the amount of light) will be different, albeit practically unidentifiable to participants.; Drug: Melantonin Placebo; Melatonin placebo dosing will be one placebo tablet once daily consumed 2 hours before the participant's desired bedtime.; Device: Tailored lighting (TL) Placebo; TL will be delivered similarly to both active and placebo groups, but the circadian stimulus (the amount of light) will be different, albeit practically unidentifiable to participants.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total number of participants enrolled in each Appendix	Total number of participants enrolled in each Appendix will be reported. Appendix-specific outcome measure data will be reported under the associated NCT#.	12 months

Collaborators and Investigators

• Sponsor: Duke University
• Investigators: Study Chair: Christina Barkauskas, MD, Duke Clinical Research Institute; Study Chair: Susan Redline, MD MPH, Brigham and Women's Hospital

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2024
• Primary Completion (Actual): December 31, 2025
• Study Completion (Actual): December 31, 2025

Study Registration Dates

• First Submitted: May 6, 2024
• First Submitted That Met QC Criteria: May 6, 2024
• First Posted (Actual): May 8, 2024

Study Record Updates

• Last Update Posted (Actual): January 22, 2026
• Last Update Submitted That Met QC Criteria: January 21, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: PASC
• Additional Relevant MeSH Terms: Post-Infectious Disorders; COVID-19; Nervous System Diseases; Mental Disorders; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Sleep Wake Disorders; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Sleep Disorders, Intrinsic; Dyssomnias; Pathological Conditions, Signs and Symptoms; Post-Acute COVID-19 Syndrome; Parasomnias; Disorders of Excessive Somnolence; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Indoles; Benzene Derivatives; Tryptamines; Benzhydryl Compounds; Modafinil; Melatonin; solriamfetol
• Other Study ID Numbers: Pro00112484; OTA-21-015G (Other Identifier: NIH Grant to RTI; RTI subcontracting with DCRI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The summary of results will be shared on the study website: https://recovercovid.org/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No