RECOVER-NEURO: Platform Protocol to Measure the Effects of Cognitive Dysfunction Interventions on Long COVID Symptoms

RECOVER-NEURO: A Platform Protocol for Evaluation of Interventions for Cognitive Dysfunction in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)

This platform protocol is designed to be flexible so that it is suitable for a wide range of settings within health care systems, for remote settings, and in community settings where it can be integrated into COVID-19 programs and subsequent treatment plans.

This protocol is a prospective, multi-center, multi-arm, randomized, controlled platform trial evaluating potential interventions for PASC-mediated cognitive dysfunction. The hypothesis is that PASC associated dysfunction in cognitive domains, such as executive function and attention, may be improved by interventions that selectively focus on enhancing those domains.

Study Overview

• Status: Completed
• Conditions: Long COVID; Long COVID-19; Long COVID19
• Intervention / Treatment: Other: BrainHQ/Active Comparator Activity; Other: BrainHQ; Device: tDCS-active; Device: tDCS-sham; Other: PASC CoRE

Detailed Description

Participants will be randomized to one of the intervention appendices that are actively enrolling at the time of randomization. Intervention appendices may be added or removed according to adaptive design and/or emerging evidence. Various interventions will be studied.

• Study Type: Interventional
• Enrollment (Actual): 328
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner University Medical Center Phoenix
    • Tucson, Arizona, United States, 85719
      • Banner University Medical Center- Tucson
  • California
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • Stanford, California, United States, 94305
      • Stanford University
    • Torrance, California, United States, 90509
      • Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus
  • Florida
    • Jacksonville, Florida, United States, 32256
      • University of Florida College of Medicine Jacksonville
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Peoria, Illinois, United States, 61801
      • OSF Healthcare
    • Skokie, Illinois, United States, 60076
      • North Shore University Health System/Evanston Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Silver Spring, Maryland, United States, 20904
      • Jadestone Clinical Research
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Daeconess Medical Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New York
    • Brooklyn, New York, United States, 11220
      • NYU Langone Health/Brooklyn Hospital
    • New York, New York, United States, 10029
      • Icahn School Of Medicine At Mount Sinai
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospitals and Clinics
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia Clinical and Translational Science Institute

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. PROMIS-Cog T-score < 40

3. 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 clinical OR epidemiological criteria:

   a. 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; b. Epidemiological criteria: Contact of a probable or confirmed case or linked to a COVID-19 cluster;

   B. Presented acute respiratory infection with history of fever or measured fever of ≥ 38°C and cough, with onset within the last 10 days, and who requires 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 clinical criteria above AND was a contact of a probable or confirmed case or was linked to a COVID-19 cluster.

   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 AND/OR epidemiological criteria (See suspected case A.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.

4. Cognitive dysfunction symptoms following a SARS-CoV-2 infection that have persisted for at least 12 weeks and are still present at the time of consent
5. Fluent in English or Spanish language
6. Willing and able to provide informed consent, complete the intervention, complete the intervention assessments, and return for all of the necessary follow-up visits

Exclusion Criteria:

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

1. Prior or active unstable or progressive major psychiatric or neurologic condition that would not show improvement and could hide treatment effect and is not related to SARS-CoV-2 infection, at the investigator's discretion, including, but not limited to, the following examples:

   a. Progressive neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease, etc.

   b. Past traumatic brain injury occurrence still associated with active post-concussive symptoms c. Uncontrolled seizure disorder, such as having at least one seizure in the last year that is adjudicated by clinical judgement d. Post-stroke deficits that may interfere with assessment, such as language or communication difficulties, aphasia, etc.

   e. Formal thought disorders, such as schizophrenia, etc. f. Any neuropsychiatric or neurologic disorder uncontrolled for the previous six months or that may interfere with assessment, at discretion of the investigator

2. Known prior diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome, not related to SARS-CoV-2 infection
3. Known active acute SARS-CoV-2 infection ≤ 4 weeks from consent
4. Current use of symptomatic therapies including prescribed or illicit stimulants, amantadine, N-methyl-D-aspartate receptor antagonists (e.g., memantine, dissociative drugs)
5. Current use of a stimulant for treating any PASC-related symptom

6. Current diagnosis of alcohol and substance use disorders

   a. Prior use disorders acceptable if abstinence achieved and maintained for at least 12 months before study enrollment

7. Insufficient visual, auditory, and motor function to participate in intervention and assessments
8. Known pregnancy
9. Current or recent use (within the last 2 months) of intervention*
10. Known allergy/sensitivity/hypersensitivity to components of the intervention or comparator*
11. Currently receiving/using intervention from another clinical trial, such as another RECOVER trial

12. Any condition that would make the participant, in the opinion of the investigator, unsuitable for the study

    1. The site investigator has the discretion to determine whether a participant is too cognitively impaired to participate and should instead be referred for clinical evaluation.

Exclusions specific to intervention appendices are listed in each appendix.

* Relevant if only one intervention appendix is open at the time of enrollment, though exclusion may be qualified in the appendix. If multiple intervention appendices are open, a participant may be excluded from any intervention appendix based on contraindications listed in the intervention appendix, current use of intervention, or known allergy/sensitivity/hypersensitivity and still remain eligible for the remaining 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

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: BrainHQ Active Comparator; 5 sessions/week at 30 min/session	Other: BrainHQ/Active Comparator Activity; BrainHQ platform provides a set of cognitive activities, like puzzles and games, that are cognitively stimulating and actively engage participants but do not continuously and adaptively challenge them. These activities are designed to be a face-valid, active comparison approach to cognitive therapy, thus participants are blinded, attention time is matched, and overall user experience is identical to the active arms.
Experimental: BrainHQ; 5 sessions/week at 30 min/session	Other: BrainHQ; BrainHQ is an online cognitive training program, and has been used to improve cognitive function among persons with cognitive impairment based on principles of neuroplasticity.
Experimental: Brain HQ + tDCS-active; 2.0 mA stimulation delivered for 30 min during each BrainHQ session	Other: BrainHQ; BrainHQ is an online cognitive training program, and has been used to improve cognitive function among persons with cognitive impairment based on principles of neuroplasticity.; Device: tDCS-active; Transcranial direct current stimulation (tDCS) will use a device specifically for home-based use. This device delivers a weak electrical current of 2.0 mA passed through two electrodes placed on the scalp to target the dorsolateral prefrontal cortex region of the brain. The electrodes are single-use for each session and can be attached to a headset by snapping into place. The device has a user-friendly interface and a large-button keypad, making it is easy to use at home.
Placebo Comparator: Brain HQ + tDCS-sham; Inactive stimulation delivered for 30 min during each BrainHQ session	Other: BrainHQ; BrainHQ is an online cognitive training program, and has been used to improve cognitive function among persons with cognitive impairment based on principles of neuroplasticity.; Device: tDCS-sham; tDCS devices used in the sham arm will be pre-programmed to deliver the same ramp up/down at the beginning/end of the 30-minute period as the active arm, except with no current otherwise delivered during the session.
Experimental: BrainHQ + PASC CoRE; BrainHQ plus 9 group sessions at 1.5 hr/session and 3 individual sessions at 30 min/session	Other: BrainHQ; BrainHQ is an online cognitive training program, and has been used to improve cognitive function among persons with cognitive impairment based on principles of neuroplasticity.; Other: PASC CoRE; PASC CoRE is a manualized, adaptable cognitive rehabilitation intervention adapted from Goal Management Training and other evidence based programs that improve attention and executive functions, among other cognitive domains.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of Participants Enrolled in Each Appendix	Appendix-specific outcome measure data will be reported under the associated NCT ID.	160 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PROMIS-cognitive function - short form 8a (PROMIS-Cog) total score	The PROMIS-Cog is the PROMIS short form for the cognitive function domain and is a self-report, 8-item questionnaire targeting cognitive function in the past seven days.	Baseline, EOI (Day 70), End of Study (EOS) (Day 160)
Change on an objective neurocognitive battery scores		Baseline, EOI (Day 70), EOS (Day 160)
Change in Everyday Cognition 2 (ECog2)	Everyday Cognition 2 (ECog2) is a self-report, 41-item questionnaire used to measure the participant's simple reaction time; respond when X happens and Choice reaction time; respond only if X happens.	Baseline, EOS (Day 160)
Characterize the intervention's safety as measured by the proportion of Serious Adverse Events, Unanticipated Adverse device Effects, and/or Events of Special Interest [Proportion of SAEs, UADEs, and/or ESIs.]		Baseline to EOS (Day 160)

Collaborators and Investigators

• Sponsor: Duke University
• Investigators: Study Chair: Kanecia Zimmerman, MD PhD, Duke University; Study Chair: Daniel Laskowitz, MD MHS, Duke University

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2023
• Primary Completion (Actual): June 10, 2024
• Study Completion (Actual): June 10, 2024

Study Registration Dates

• First Submitted: July 25, 2023
• First Submitted That Met QC Criteria: July 25, 2023
• First Posted (Actual): July 28, 2023

Study Record Updates

• Last Update Posted (Actual): July 18, 2025
• Last Update Submitted That Met QC Criteria: July 17, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Cognitive; PASC
• Additional Relevant MeSH Terms: Post-Infectious Disorders; Mental Disorders; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Neurocognitive Disorders; Lung Diseases; Cognition Disorders; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; Post-Acute COVID-19 Syndrome; Cognitive Dysfunction
• Other Study ID Numbers: Pro00112477; 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 investigators will share the summary of results on the study website: https://recovercovid.org/

Drug and device information, study documents

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