RECOVER-SLEEP

Currently Recruiting: Sites and Participants

Study Drug/Intervention:

• Appendix A: modafinil vs placebo or solriamfetol versus placebo (if modafinil is contraindicated).
• Appendix B: all participants will receive RESET-PASC, a behavioral education, and Melatonin + Light --or--​ Melatonin + Placebo Light --or--​ Placebo Melatonin + Light --or--​ Placebo Melatonin + Placebo Light

Anticipated Sample Size: 1,074 (474 Appendix A participants and 600 Appendix B participants)

Study Timeline: 12 months beginning July 2024

ClinicalTrials.gov ID:  NCT06404086

What is RECOVER-SLEEP?

This platform protocol is a prospective, multi-center, multi-arm, randomized controlled platform trial evaluating potential interventions for post-acute sequelae of SARS-CoV-2 infection (PASC)-mediated sleep disturbances. The hypothesis is that phenotype-targeted interventions can improve symptoms of sleep and circadian disorders that emerge in patients with PASC. Specific sleep and circadian disorders addressed in this protocol include sleep-related daytime impairment (hypersomnia) and complex PASC-related sleep disturbance (reflecting symptoms of insomnia and sleep-wake rhythm disturbance).

Study Objective

Evaluate the efficacy of study intervention versus control on sleep-related daytime impairment, sleep disturbance, and/or sleep-wake rhythm disturbance.

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:
   1. 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
   2. Presented with acute respiratory infection with a history of fever or measured fever of ≥38 °C (100.4 °F) and cough, with onset within the last 10 days, and required hospitalization; or
   3. 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.
3. 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:
   1. Presented with a positive nucleic acid amplification test, regardless of clinical criteria OR epidemiological criteria; or
   2. 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.
4. New/worse sleep problems following a SARS-CoV-2 infection that have persisted for at least 12 weeks38 and are still present at the time of consent
5. PROMIS 8a SRI or 8b SD T score ≥60
   1. If the PROMIS 8a SRI is ≥60, participants must also self-report symptoms of trouble staying awake, feeling too sleepy, or falling asleep unintentionally during the day over the preceding 12 weeks, and these symptoms either started after a SARS-CoV-2 infection, or if they preceded a SARS-CoV-2 infection, must have mostly worsened since the infection. These PRO outcomes and patient responses suggest a hypersomnia phenotype.
   2. If the PROMIS 8b SD is ≥60, participants must also self-report symptoms of trouble falling asleep, staying asleep, or frequently waking from sleep over the preceding 12 weeks, and these symptoms either started after a SARS-CoV-2 infection, or if they preceded a SARS-CoV-2 infection, must have mostly worsened since the infection. These PRO outcomes and patient responses suggest an insomnia or circadian rhythm disorder phenotype.
6. Willing and able to provide informed consent, complete the surveys and clinical assessments, and return for all of the necessary follow-up visits
7. Adequate method of birth control for participants of child-bearing potential

* 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.

Exclusion Criteria

Please note there is a platform-level and appendix-level

An individual who meets any of the following criteria will be excluded from participation in this study (though participants may be re-screened at the site investigator’s discretion):

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 SRBDs
   1. OSA (apnea-hypopnea index/respiratory event index ≥15)
   2. CSA (central apnea index ≥10)
   3. Cheyne-Stokes breathing >10 minutes)
   4. percentage estimated sleep time at an oxyhemoglobin saturation <88% (T88) >10% unexplained by an elevated apnea-hypopnea index
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 disorders, 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
12. Any condition that would make the participant, in the opinion of the site investigator, unsuitable for the study

* An exclusion from the platform protocol if only one study intervention appendix is open at 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. 

Additional Appendix-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 (> one year), unstable angina, serious cardiac arrhythmias, or other serious heart problems at the discretion of the investigator; refer to the MOP for details.
6. Current use of stimulant or wake-promoting medications, unless a washout is permitted; refer to the MOP.
7. Regular use of prescribed hypnotics for sleep (≥ three times per week); washout period is permitted.

Refer to the MOP for a list of hypnotics.

*Characterized by the screening labs: coagulation panel and CMP w/LFTs

13.2.1 MODAFINIL EXCLUSION CRITERIA

1. Modafinil can affect drug metabolism given its effect on enzymes such as CYP3A4 and CYP2C19.
   • To assess drug interactions, investigators should use the Lexicomp Drug Interactions System, which is available at most institutions.
   • 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.
   • See the MOP for examples of common drugs that fall into these categories.
2. Known severe left ventricular hypertrophy and mitral valve prolapse; see the MOP for definitions.

13.2.2 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

Additional Appendix-Level Exclusion Criteria 

The following additional exclusion criteria are to be considered together to determine eligibility. They are separated here by TL and melatonin only for presentation. RESET-PASC presents no additional exclusions.

14.2.1 TAILORED LIGHTING EXCLUSION CRITERIA

1. Severe visual impairments affecting sensitivity or ability to respond to light
2. Severe photosensitivity dermatitis
3. Severe progressive retinal disease, e.g., macular degeneration
4. Permanently dilated pupil, e.g., following certain cataract surgeries
5. Unwilling to remove or not wear blue-light-blocking glasses during TL dosing

14.2.2 MELATONIN EXCLUSION CRITERIA

1. Sleep medication, if not willing, to wash out for four weeks. Please see the MOP for a detailed list of prohibited medications.

This platform will enroll adult participants who have persistent symptoms of various sleep disturbances. Overall enrollment will depend on the number of screen failures, the number of study intervention appendices that are added, the ability to pool their control groups for analysis, and adjustments to sample size based on study data. The goal is to have a diverse population, including underserved communities and racial/ethnic populations frequently underrepresented in clinical research.

Study Duration

The duration of each intervention will be appendix-specific. An end-of-study visit will occur for all interventions approximately 30 days after the end of the intervention. Study participation will last for the pre-randomization period, the duration of the intervention, and until the end-of-study visit.

Study Follow-Up

Participants will be contacted via phone 30 days post-intervention.

National Institutes of Health

For more information, please contact recover-sleep@duke.edu.