RECOVER-SLEEP: Platform Protocol, Appendix_A (Hypersomnia)

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: Active, not recruiting
• Conditions: Long COVID; Long COVID-19; Hypersomnia
• Intervention / Treatment: 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): 361
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • All sites listed under NCT06404086

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• See NCT06404086 for RECOVER-SLEEP: Platform Protocol level inclusion criteria which applies to this appendix

Exclusion Criteria:

• See NCT06404086 for RECOVER-SLEEP: Platform Protocol level exclusion criteria which applies to this appendix (or sub-study)

Additional Appendix A (Hypersomnia) Level Exclusion Criteria:

1. Self-reported sleep duration <6 hours per night
2. Poorly controlled hypertension (systolic blood pressure ≥140 or diastolic blood pressure ≥90 mmHg)
3. Moderate to severe hepatic impairment (ie, Child-Pugh class B or C)*
4. Known estimated glomerular filtration rate <30 mL/min/1.73 m2 and/or chronic dialysis*
5. Recent myocardial infarction (<1 year), unstable angina, serious cardiac arrhythmias, or other serious heart problems, at the discretion of the investigator
6. Current use of stimulant or wake-promoting medications, unless a washout is permitted

7. Regular use of prescribed hypnotics for sleep (≥3 times per week); washout period is permitted.

   • characterized by the screening labs: coagulation panel and CMP w/LFTs

MODAFINIL EXCLUSION CRITERIA

1. Modafinil can affect drug metabolism given its effect on enzymes such as CYP3A4 and CYP2C19. To assess for drug interactions, investigators should use the Lexicomp Drug Interactions System that is available at most institutions.

   o If the search yields "D" - Consider Modifying Therapy or "X" - Avoid Combination, then the ACTION is to exclude the potential participant.

   An important example of this is steroid hormonal contraceptives.

   • If the search yields "C" - Monitor Therapy, then discuss with site PIs on a case-by-case basis.
   • If the search yields "A" - No Known Interaction or "B" - No Action Needed, then proceed to screen/include the potential participant.
2. Known severe left ventricular hypertrophy, mitral valve prolapse

SOLRIAMFETOL EXCLUSION CRITERIA

1. Concurrent treatment with a monoamine oxidase inhibitor (MAOI) or use of an MAOI within the preceding 14 days
2. Current use of dopaminergic drugs

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
Active Comparator: Wake-promoting drug: Modafinil or solriamfetol; Participants in Appendix A will be randomized to study drug or control. Participants who meet the eligibility criteria for modafinil will receive either active modafinil or the modafinil-matched control. If modafinil is contraindicated for any reason, participants will be assessed for their ability to take solriamfetol. If participants are eligible for solriamfetol, they will receive either active solriamfetol or the 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.	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: 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.
Placebo Comparator: Modafinil-matched placebo or solriamfetol-matched placebo; Participants in Appendix A will be randomized to study drug or control. Participants who meet the eligibility criteria for modafinil will receive either active modafinil or the modafinil-matched control. If modafinil is contraindicated for any reason, participants will be assessed for their ability to take solriamfetol. If participants are eligible for solriamfetol, they will receive either active solriamfetol or the 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.	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 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in total score of the PROMIS 8a SRI to assess sleep-related impairment	The PROMIS 8a SRI form includes a total of 8 items that ask participants to reflect on their sleep-related daytime impairment over the past 7 days with questions rated not at all to very much. T-Scores range from 0 to 100, with a score of 55 being 1 standard deviation above population mean. Higher scores indicate greater sleep-related impairment.	Baseline, End of Intervention (Day 77)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PROMIS 10a Fatigue score	The PROMIS 10a Fatigue is a 10-item questionnaire that assesses a participant's fatigue on a scale of 1 (not at all fatigued) to 5 (very much).	Baseline, End of Intervention (Day 77)
Change in an objective neurocognitive battery score		Baseline, End of Intervention (Day 77)
Change in ECog2 measure	Everyday Cognition 2 (ECog2) is a self-report, 41-item questionnaire used to measure measure the participant's perceived capacity to perform activities related to cognitive function, which could impact major activities of daily living and independence. It has been used for patients with mild cognitive impairment, Alzheimer's Disease, and dementia. It takes 5 minutes to complete.	Baseline, End of Intervention (Day 77)
Change in PASC Symptom Questionnaire responses	Participants will be asked to complete a questionnaire that asks about the presence of PASC symptoms at Baseline and at follow-up visits. This questionnaire includes symptoms that have been associated with PASC.	Baseline, End of Intervention (Day 77)
Change in total score on the Insomnia Severity Index (ISI)	The ISI is a 7-item, self-report questionnaire that assesses the nature, severity, and impact of insomnia, on a 5-point Likert scale (eg, 0 = not at all, 4 = extremely; scores: from 0 to 28). The ISI asks patients to recall their insomnia symptoms over the past 2 weeks.	Baseline, End of Intervention (Day 77)
Change in within-person variability (over a 7-day period) in sleep onset time, assessed by sleep diary	Sleep onset time will be assessed by sleep diary	Baseline, End of Intervention (Day 77)
Change in average (over a 7-day period) nocturnal sleep duration, assessed by sleep diary	Nocturnal sleep duration will be assessed by sleep diary	Baseline, End of Intervention (Day 77)
Change in average (over a 7-day period) 24-hour sleep duration, assessed by sleep diary	24-hour sleep duration will be assessed by sleep diary	Baseline, End of Intervention (Day 77)
Change in average (over a 7-day period) sleep midpoint, assessed by sleep diary	Sleep midpoint is the time half way between start and end of sleep, as assessed by sleep diary	Baseline, End of Intervention (Day 77)
Change in average (over a 7-day period) nocturnal sleep duration, assessed by activity tracker	Nocturnal sleep duration will be assessed by activity tracker	Baseline, End of Intervention (Day 77)
Change in average (over a 7-day period) 24-hour sleep duration, assessed by activity tracker	24-hour sleep duration will be assessed by activity tracker	Baseline, End of Intervention (Day 77)
Change in average (over a 7-day period) sleep efficiency, assessed by activity tracker	Sleep Efficiency is the percentage of the sleep period spent asleep, as measured by activity tracker	Baseline, End of Intervention (Day 77)
Change in average (over a 7-day period) sleep midpoint, assessed by activity tracker	Sleep midpoint is the time half way between start and end of sleep, as assessed by sleep diary	Baseline, End of Intervention (Day 77)
Change in total score of the PROMIS 8b SD to assess sleep disturbance	The PROMIS 8b SD form includes a total of 8 items that ask participants to reflect on their sleep over the past 7 days with one question rated very poor to very good and the remaining questions rated not at all to very much. T-Scores range from 0 to 100, with > 55 1 SD above population mean.	Baseline, End of Intervention (Day 77)

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): August 12, 2024
• Primary Completion (Estimated): March 18, 2026
• Study Completion (Estimated): April 15, 2026

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; Disorders of Excessive Somnolence; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Benzene Derivatives; Benzhydryl Compounds; Modafinil; solriamfetol
• Other Study ID Numbers: Pro00112484_A; OTA-21-015G (Other Grant/Funding Number: 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: No
• product manufactured in and exported from the U.S.: No