This study is a platform protocol designed to be flexible so that it is suitable for awide range of settings within health care systems and in community settings where it canbe integrated into COVID-19 programs and subsequent treatment plans.This protocol is a prospective, multi-center, multi-arm, randomized, controlled platformtrial evaluating various interventions for use in the treatment of autonomic dysfunctionsymptoms, including cardiovascular complications and postural orthostatic tachycardiasyndrome (POTS), in PASC participants. The interventions tested will includenon-pharmacologic care and pharmacologic therapies with study drugs.
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.
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: 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: 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.
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.
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
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
Lakeland Regional Medical Center - Appendix A & B
Lakeland, Florida, United States
Innovation Clinical Trials Inc.- Appendix A & B
Palmetto Bay, Florida, United States
Grady Memorial Hospital - Woodruff Memorial Research - Appendix A & B
Atlanta, Georgia, United States
Morehouse School of Medicine - Appendix A & B
Atlanta, Georgia, United States
Queens Medical Center - Appendix B Only
Honolulu, Hawaii, United States
Rush University Medical Center - Appendix B Only
Chicago, Illinois, United States
University of Illinois at Chicago - Appendix A & B
Chicago, Illinois, United States
NorthShore University HealthSystem - Evanston Hospital - Appendix B Only
Evanston, Illinois, United States
University of Iowa - Appendix A & B
Iowa City, Iowa, United States
University of Kansas Medical Center CTSU Fairway - Appendix A & B
Fairway, Kansas, United States
University of Kentucky Medical Center - Appendix A & B
Lexington, Kentucky, United States
University Medical Center New Orleans - Appendix A & B
New Orleans, Louisiana, United States
Johns Hopkins Hospital - Appendix A Only
Baltimore, Maryland, United States
Brigham and Women's Hospital - Appendix A Only
Boston, Massachusetts, United States
Henry Ford Hospital - Appendix A & B
Detroit, Michigan, United States
Mayo Clinic - Appendix A & B
Rochester, Minnesota, United States
University of Mississippi Medical Center - Appendix A & B
Jackson, Mississippi, United States
Washington University School of Medicine - Appendix B Only
Saint Louis, Missouri, United States
Montefiore Medical Center - Moses Campus - Appendix B
Bronx, New York, United States
University at Buffalo - Appendix A & B
Buffalo, New York, United States
St. Lawrence Health Medical Campus - Appendix A & B
Canton, New York, United States
Columbia University Irving Medical Center - Appendix A & B
New York, New York, United States
Stony Brook University Hospital - Appendix A & B
Stony Brook, New York, United States
Duke University Hospital - Appendix A & B
Durham, North Carolina, United States
East Carolina University - Appendix B Only
Greenville, North Carolina, United States
Cleveland Clinic - Appendix A & B
Cleveland, Ohio, United States
University of Oklahoma Health Science Center - Oklahoma Clinical and Translational Science Institute - Appendix A & B
Oklahoma City, Oklahoma, United States
Oregon Health and Science University - Appendix A & B
Portland, Oregon, United States
Kent Hospital - Appendix A & B
Pawtucket, Rhode Island, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
National Neuromuscular Research Institute - Appendix A & B
Austin, Texas, United States
Southwest Family Medicine Associates - Appendix A & B
Dallas, Texas, United States
University of Texas Health Science Center at Houston
Houston, Texas, United States
University of Texas Health Science Center at San Antonio - Appendix A & B
San Antonio, Texas, United States
Bateman Horne Center - Appendix B Only
Salt Lake City, Utah, United States
Vermont Lung Center, University of Vermont - Appendix B Only
Burlington, Vermont, United States
University of Virginia Health System, University Hospital - Appendix A & B
Charlottesville, Virginia, United States
Sentara Norfolk General Hospital - Appendix A & B
Norfolk, Virginia, United States
Evergreen Hospital Medical Center - Appendix A & B
Kirkland, Washington, United States
Providence Medical Research Center - Appendix A & B
Spokane, Washington, United States
Marshall Health - University Physicians and Surgeons - Appendix A & B
Huntington, West Virginia, United States
Orshi Moy
919-668-8060
recoverresearch@duke.edu
Barrie L Harper, BSMT (ASCP) PMP
recoverresearch@duke.edu