RECOVER-AUTONOMIC Platform Protocol (RECOVER-AUTO)

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

This study is a platform protocol designed to be flexible so that it is suitable for a wide range of settings within health care systems 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 various interventions for use in the treatment of autonomic dysfunction symptoms, including cardiovascular complications and postural orthostatic tachycardia syndrome (POTS), in PASC participants. The interventions tested will include non-pharmacologic care and pharmacologic therapies with study drugs.

Study Overview

• Status: Completed
• Conditions: Long COVID; Long Covid19; Long Covid-19
• Intervention / Treatment: Drug: IVIG + Coordinated Care; Drug: IVIG Placebo + Coordinated Care; Drug: IVIG + Usual Care; Drug: IVIG Placebo + Usual Care; Drug: Ivabradine + Coordinated Care; Drug: Ivabradine Placebo + Coordinated Care; Drug: Ivabradine + Usual Care; Drug: Ivabradine Placebo + Usual Care

Detailed Description

The hypothesis is that some of the autonomic dysfunction symptoms are immune-mediated, so immunotherapy and other applicable therapies will result in improvement in autonomic symptoms.

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.

• Study Type: Interventional
• Enrollment (Actual): 381
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Opelika, Alabama, United States, 36801
      • East Alabama Medical Center - Appendix B Only
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Center for Complex Neurology - Appendix A & B
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences - Appendix A & B
  • California
    • La Jolla, California, United States, 92307
      • University of California San Diego - Appendix B Only
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center - Appendix A & B
    • Stanford, California, United States, 94305
      • Stanford University - Appendix B Only
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus Clinical and Translational Research Center (CTRC) - Appendix A & B
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • MedStar National Rehabilitation Hospital - Appendix B only
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Health - Appendix A & B
    • Lakeland, Florida, United States, 33805
      • Lakeland Regional Medical Center - Appendix A & B
    • Palmetto Bay, Florida, United States, 33157
      • Innovation Clinical Trials Inc.- Appendix A & B
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital - Woodruff Memorial Research - Appendix A & B
    • Atlanta, Georgia, United States, 30310
      • Morehouse School of Medicine - Appendix A & B
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Queens Medical Center - Appendix B Only
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center - Appendix B Only
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago - Appendix A & B
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem - Evanston Hospital - Appendix B Only
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa - Appendix A & B
  • Kansas
    • Fairway, Kansas, United States, 66205
      • University of Kansas Medical Center CTSU Fairway - Appendix A & B
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Medical Center - Appendix A & B
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • University Medical Center New Orleans - Appendix A & B
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital - Appendix A Only
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital - Appendix A Only
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital - Appendix A & B
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Appendix A & B
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center - Appendix A & B
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine - Appendix B Only
  • New York
    • Buffalo, New York, United States, 14203
      • University at Buffalo - Appendix A & B
    • Canton, New York, United States, 13617
      • St. Lawrence Health Medical Campus - Appendix A & B
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center - Appendix A & B
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Hospital - Appendix A & B
    • The Bronx, New York, United States, 10467
      • Montefiore Medical Center - Moses Campus - Appendix B
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Hospital - Appendix A & B
    • Greenville, North Carolina, United States, 27834
      • East Carolina University - Appendix B Only
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic - Appendix A & B
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Science Center - Oklahoma Clinical and Translational Science Institute - Appendix A & B
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University - Appendix A & B
  • Rhode Island
    • Pawtucket, Rhode Island, United States, 02860
      • Kent Hospital - Appendix A & B
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States, 78759
      • National Neuromuscular Research Institute - Appendix A & B
    • Dallas, Texas, United States, 75235
      • Southwest Family Medicine Associates - Appendix A & B
    • Houston, Texas, United States, 78701
      • University of Texas Health Science Center at Houston
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio - Appendix A & B
  • Utah
    • Salt Lake City, Utah, United States, 84102
      • Bateman Horne Center - Appendix B Only
  • Vermont
    • Burlington, Vermont, United States, 05405
      • Vermont Lung Center, University of Vermont - Appendix B Only
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System, University Hospital - Appendix A & B
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk General Hospital - Appendix A & B
  • Washington
    • Kirkland, Washington, United States, 98034
      • Evergreen Hospital Medical Center - Appendix A & B
    • Spokane, Washington, United States, 99204
      • Providence Medical Research Center - Appendix A & B
  • West Virginia
    • Huntington, West Virginia, United States, 25701
      • Marshall Health - University Physicians and Surgeons - Appendix A & B

Participation Criteria

Eligibility Criteria

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

Description

Inclusion 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 Organization12ɸ ɸ Enrollment of participants with suspected or probable SARS-CoV-2 infection will only be allowed if they occurred before May 1, 2021 and be limited to no more than 10% of the total sample size per Study Drug Appendix. Refer to the Manual of Procedures (MOP) for details.

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

   A. Meets 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. Presents with 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. Presents 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 meets clinical criteria above AND is a contact of a probable or confirmed case or is linked to a COVID-19 cluster.

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

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

3. Moderate, self-identified autonomic symptoms (defined as COMPASS-31 >20) following a SARS-CoV-2 infection that has persisted for at least 12 weeks and is still present at the time of consent
4. OHQ/OIQ, question 1 score >2

Exclusion Criteria:

1. Known pregnancy, breast-feeding, or contemplating pregnancy during the study period
2. Known active acute SARS-CoV-2 infection ≤ 4 weeks from enrollment
3. Known renal failure (eGFR <20ml/1.73 m²)
4. Known atrial fibrillation or significant cardiac arrhythmia
5. Known cardiovascular conditions such as heart failure (Class 3-4), severe valvular disease
6. Clinically significant atherosclerotic disease, defined as history of stroke or myocardial infarction or revascularization 6 months prior to enrollment and/or current symptomatic angina
7. Existing uncontrolled hypertension
8. Inability to comply with the protocol
9. Any condition that the investigator believes makes it inappropriate to treat with study intervention, including severe debility.
10. History of POTS or significant dysautonomia before COVID-19 index infection
11. Enrolled in another clinical trial or another study intervention appendix in this platform protocol * Patients who are a part of observational studies (e.g. imaging) may be included in this trial. Participants may enroll in another interventional trial or re-enroll in this trial for a different study intervention appendix 30 days after end of study (Follow-up visit).

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
Experimental: IVIG; In the IVIG study, randomization will be implemented with 1:1:1:1 allocation among the combination of IVIG/placebo and coordinated/ usual non-pharmacologic care. All participants will receive IVIG or placebo for 9 months (36 weeks) with a follow-up period for an additional 3 months (total study duration for 12 months). See NCT06305793 for additional details.	Drug: IVIG + Coordinated Care; Participants will receive IVIG for a duration of 9 months and coordinated non-pharmacologic care for a duration of 3 months, concurrent with IVIG administration. Coordinated non-pharmacologic care involves volume expansion through high salt diet, water intake, abdominal binder, exercise/rehabilitation, motivation, education, and assisted care through a care coordinator.; Drug: IVIG Placebo + Coordinated Care; Normal saline given intravenously will be the control (placebo) product. Blinding IV bag and tubing covers will be used for both IVIG and Placebo administration. Participants will receive IVIG placebo for a duration of 9 months and coordinated non-pharmacologic care for a duration of 3 months, concurrent with IVIG placebo administration. Coordinated non-pharmacologic care involves volume expansion through high salt diet, water intake, abdominal binder, exercise/rehabilitation, motivation, education, and assisted care through a care coordinator.; Drug: IVIG + Usual Care; Participants will receive IVIG for a duration of 9 months and usual non-pharmacologic care (control) for a duration of 3 months. This will be concurrent with scheduled IVIG administration.; Drug: IVIG Placebo + Usual Care; Normal saline given intravenously will be the control (placebo) product. The normal saline will be of similar formulation and appearance to IVIG. Participants will receive IVIG placebo for a duration of 9 months and usual non-pharmacologic care (control) for a duration of 3 months. This will be concurrent with scheduled IVIG placebo administration.
Experimental: Ivabradine; In the ivabradine study, randomization will be implemented with 1:1:1:1 allocation among the combinations of ivabradine/placebo and coordinated/usual care. All participants receive either ivabradine or placebo for 3 months (12 weeks) with a follow-up period for an additional 3 months (total study duration of 6 months). See NCT06305806 for additional details.	Drug: Ivabradine + Coordinated Care; Participants will receive Ivabradine for a duration of 3 months and coordinated non-pharmacologic care for a duration of 3 months, concurrent with ivabradine administration. Coordinated non-pharmacologic care involves volume expansion through high salt diet, water intake, abdominal binder, exercise/rehabilitation, motivation, education, and assisted care through care coordinator.; Drug: Ivabradine Placebo + Coordinated Care; The control (placebo) oral tablets will be similar to the study drug, ivabradine. The control packaging matches the packaging. Participants will receive Ivabradine placebo for a duration of 3 months and coordinated non-pharmacologic care for a duration of 3 months, concurrent with ivabradine placebo administration. Coordinated non-pharmacologic care involves volume expansion through high salt diet, water intake, abdominal binder, exercise/rehabilitation, feedback, nutrition counseling, motivation, education, and assisted care through care coordinator.; Drug: Ivabradine + Usual Care; Participants will receive Ivabradine for a duration of 3 months and usual non-pharmacologic care (control) for a duration of 3 months, concurrent with ivabradine administration.; Drug: Ivabradine Placebo + Usual Care; The control (placebo) oral tablets will be similar to the study drug, ivabradine. The control packaging matches the packaging. Participants will receive Ivabradine placebo for a duration of 3 months and usual non-pharmacologic care (control) for a duration of 3 months, concurrent with ivabradine placebo administration.

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#	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Composite Autonomic Symptoms Score 31 (COMPASS-31)	The COMPASS-31 is a patient reported outcome that measures autonomic symptoms across multiple domains commonly seen in patients with PASC. Scores range from 0-100 with higher values representing severe symptoms.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Change in Malmo POTS Symptom Score	The Malmo POTS symptom score assesses symptom burden in postural orthostatic tachycardia syndrome (POTS). It is a self-rating, 12-item score (0-10 per item, total range 0-120) based on patients' own perception of symptoms through visual analogue scale assessment. Higher scores represent more pronounced symptoms.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Change in Active Stand Test	Participants will remain supine for 10 minutes, and data will be acquired at 5 and 10 minutes. Standing test should be performed with HR and BP monitoring at 1, 3, 5 and 10 minutes	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Change in blood pressure	measured from Active stand test	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Change in heart rate (HR)	measured from Active stand test	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Change in 6-min Walk Test	Normal walking speed will be measured using a standard 6 minute walk	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Change in PROMIS-29 + 2 Questionnaire	The PROMIS-29 consists of 29 items that assess general domains of health and functioning, including overall physical health, mental health, social health, pain, fatigue, and overall perceived quality of life. The PROMIS-29+2 is used to calculate a preference score (PROPr) by the addition of two Cognitive Function Ability items. Scores will be reported as T scores ranging from 0 to 100, with a score of 60 being 1 standard deviation above the mean. Higher scores indicate worse overall health.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Change in step count as measured by a wearable device	measured by activity tracker	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Change in heart rate as measured by a wearable device	measured by activity tracker	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Proportion of participants who experience individual SAEs	These will be analyzed in the safety population.	Baseline to Follow-up (IVIG 12 months, Ivabradine 6 months)
Proportion who experience any one or more SAEs	These will be analyzed in the safety population.	Baseline to Follow-up (IVIG 12 months, Ivabradine 6 months)
Incidence of SAEs leading to discontinuation	These will be analyzed in the safety population.	Baseline to Follow-up (IVIG 12 months, Ivabradine 6 months)
Incidence of Events of Special Interest (ESIs)	Each study drug may have a unique list of ESIs	Baseline to Follow-up (IVIG 12 months, Ivabradine 6 months)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Autonomic Function Testing	Head-up tilt (HUT) test; Valsalva maneuver with a pressure of 40 mmHg for 15 seconds; Deep breathing test; Skin biopsy (if applicable as per Appendix); Transcranial doppler (TCD), if available	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Change in Vanderbilt Orthostatic Symptoms Score (VOSS)	The VOSS consists of 9 orthostatic symptoms rated on a scale of 0 (no symptom) to 10 (worst the participant has experienced) at the end of each Head-up Tilt test. Scores range from 0-90 with higher scores representing worse symptoms.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)
Change in PASC Symptom Questionnaire	Participants will be asked to complete a questionnaire that asks about the presence of PASC symptoms. This questionnaire includes additional PASC symptoms that are not directly related to autonomic dysfunction.	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)

Collaborators and Investigators

• Sponsor: Kanecia Obie Zimmerman
• Investigators: Study Chair: Cyndya Shibao, MD, Vanderbilt University Medical Center; Study Chair: Peter Novak, MD, Harvard; Study Chair: Pam Taub, MD, University of California, San Diego; Study Chair: Tae Chung, MD, Johns Hopkins University; Study Chair: Christopher Granger, MD, Duke Clinical Research Institute

Publications and helpful links

General Publications

• Fudim M, Novak P, Taub PR, Chung T, Zimmerman KO, Moy OV, Fissler HZ, Wen J, Freeman NLB, O'Brien S, Marti H, Cook D, Low P, Kim DY, Rosenberg Y, Granger CB, Shibao CA. Design and rationale of RECOVER-AUTONOMIC: a randomized platform trial evaluating interventions for Long COVID postural orthostatic tachycardia syndrome. Am Heart J. 2026 Feb 18:107384. doi: 10.1016/j.ahj.2026.107384. Online ahead of print.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2024
• Primary Completion (Actual): July 9, 2025
• Study Completion (Actual): July 9, 2025

Study Registration Dates

• First Submitted: March 4, 2024
• First Submitted That Met QC Criteria: March 8, 2024
• First Posted (Actual): March 12, 2024

Study Record Updates

• Last Update Posted (Actual): February 20, 2026
• Last Update Submitted That Met QC Criteria: February 18, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: POTS; PASC
• Additional Relevant MeSH Terms: Post-Infectious Disorders; COVID-19; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Pathological Conditions, Signs and Symptoms; Post-Acute COVID-19 Syndrome; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Benzazepines; Immunoglobulin Isotypes; Immunoglobulin G; Immunoglobulins, Intravenous; Ivabradine
• Other Study ID Numbers: Pro00112597; 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