RECOVER-AUTONOMIC Platform Protocol

Phase 2

Recruiting

• Conditions: Long COVID; Long Covid19; Long Covid-19
• Interventions: Drug: IVIG + Coordinated Care; Drug: Ivabradine + Coordinated Care; Drug: IVIG Placebo + Coordinated Care; Drug: Ivabradine Placebo + Coordinated Care; Drug: Ivabradine + Usual Care; Drug: IVIG + Usual Care; Drug: IVIG Placebo + Usual Care; Drug: Ivabradine Placebo + Usual Care

• Registration Number: NCT06305780
• Lead Sponsor: Kanecia Obie Zimmerman

Brief Summary

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.

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 Timeline

• Study First Submitted: 2024-03-04
• Study First Submitted QC: 2024-03-08
• Study Start: 2024-03-11
• Study First Posted: 2024-03-12
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-25
• Last Update Posted: 2025-04-27
• Primary Completion: 2025-12
• Study Completion: 2026-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 380

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 >25) 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, symptomatic ischemic coronary artery disease, revascularization for PAD/CAD within the past 6 months
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. History of significant hypercoagulability disorders
9. Active or recent thrombosis

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ivabradine	Ivabradine + Usual Care	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.
IVIG	IVIG + Coordinated Care	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.
IVIG	IVIG Placebo + Coordinated Care	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.
IVIG	IVIG + Usual Care	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.
IVIG	IVIG Placebo + Usual Care	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.
Ivabradine	Ivabradine + Coordinated Care	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.
Ivabradine	Ivabradine Placebo + Coordinated Care	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.
Ivabradine	Ivabradine Placebo + Usual Care	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.

Primary Outcome Measures

Name	Time	Method
Total number of participants enrolled in each Appendix	Baseline to End of Intervention (IVIG 9 months, Ivabradine 3 months)	Total number of participants enrolled in each Appendix will be reported. Appendix-specific outcome measure data will be reported under the associated NCT#

Trial Locations

Locations (50)

Duke University Hospital - Appendix A & B; 🇺🇸 Durham, North Carolina, United States

East Alabama Medical Center - Appendix B Only; 🇺🇸 Opelika, Alabama, United States

Center for Complex Neurology - Appendix A & B; 🇺🇸 Phoenix, Arizona, United States

University of Arkansas for Medical Sciences - Appendix A & B; 🇺🇸 Little Rock, Arkansas, United States

University of California San Diego - Appendix B Only; 🇺🇸 La Jolla, California, United States

Cedars Sinai Medical Center - Appendix A & B; 🇺🇸 Los Angeles, California, United States

Stanford University - Appendix B Only; 🇺🇸 Stanford, California, United States

University of Colorado Anschutz Medical Campus Clinical and Translational Research Center (CTRC) - Appendix A & B; 🇺🇸 Aurora, Colorado, United States

MedStar National Rehabilitation Hospital - Appendix B only; 🇺🇸 Washington, District of Columbia, United States

University of Florida Health - Appendix A & B; 🇺🇸 Gainesville, Florida, United States

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