RECOVER-AUTONOMIC

Currently Recruiting: Participants

Study Drug/Intervention:

• Appendix A: Intravenous immunoglobulin (IVIG) versus placebo and non-pharmacologic coordinated care versus usual care
• Appendix B: Ivabradine versus placebo and non-pharmacologic coordinated care versus usual care

Anticipated Sample Size: 380 patients (Appendix A = 200; Appendix B = 180)

Study Timeline: This study recruited its first patient in September 2022 and is anticipated to conclude in November 2026.

ClinicalTrials.gov ID:  NCT06305780

What is RECOVER-AUTONOMIC?

This trial is a prospective, multi-center, multi-arm, randomized, controlled platform trial evaluating various interventions for treating autonomic dysfunction symptoms, including cardiovascular complications and postural orthostatic tachycardia syndrome (POTS), in post-acute sequelae of SARS-CoV-2 infection (PASC) participants. The interventions tested will include non-pharmacologic care with study drugs.

Study Objective

Primary

• Evaluate the effect of study intervention versus control on orthostatic intolerance.

Secondary

• Evaluate the effect of study intervention versus control on symptom-specific outcome measures. 
• Describe the effect of study intervention versus control on performance-based and vital sign outcome measures. 
• Evaluate the effect of study intervention versus control on quality of life. 
• Compare the effect of study intervention versus control on specific tracked measurements. 
• Characterize the safety and tolerability of study intervention for the treatment of PASC.   

Exploratory

• Evaluate the effect of study intervention versus control on autonomic function tests. 
• Evaluate the effect of study intervention versus control on relevant biomarkers.

Inclusion Criteria

PLATFORM

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 Organization12*

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

1. 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
2. Presents with acute respiratory infection with a history of fever or measured fever of ≥38°C and cough with onset within the last ten days; and who requires hospitalization); or
3. 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, is 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:

1. A person with a positive nucleic acid amplification test, regardless of clinical criteria OR epidemiological criteria, or
2. 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 

* Enrollment of participants with suspected or probable SARS-CoV-2 infection will only be allowed if they occurred before May 1, 2021, and will 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. 

IVIG-appendix

1. An abnormal active standing test is defined as the presence of orthostatic tachycardia (an increase of 30 beats per minute (bpm) or more in HR within 10 minutes upon standing without orthostatic hypotension) and experiencing orthostatic symptoms 
2. COMPASS-31 Score >40

Ivabradine-Appendix

1. An abnormal active standing test is defined as the presence of orthostatic tachycardia (an increase of 30 beats per minute (bpm) or more in HR within 10 minutes upon standing without orthostatic hypotension) and experiencing orthostatic symptoms 
2. COMPASS-31 Score >25 and not enrolled in the IVIG appendix 

Exclusion Criteria

PLATFORM

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 six months
6. Clinically significant atherosclerotic disease, defined as a history of stroke or myocardial infarction or revascularization six months prior to enrollment and/or current symptomatic angina
7. Existing uncontrolled hypertension 
8. History of significant hypercoagulability disorders
9. Active or recent thrombosis
10. Inability to comply with the protocol
11. Less than two weeks since discontinuation/weaning of beta-blockers and calcium channel blockers 
12. Any condition that the investigator believes makes it inappropriate to treat with study intervention, including severe debility.
13. History of POTS or significant dysautonomia before COVID-19 index infection.
14. Enrolled in another clinical trial or another study intervention appendix in this platform protocol

*Participants may enroll in the trial or re-enroll in the trial for a different study intervention appendix if they have completed a 30-day washout period. For those who wish to re-enroll, re-enrollment can only occur after efficacy has been determined for the appendix in which they were previously enrolled.
   
IVIG-Appendix

1. Current or previous IVIG treatment
2. Contraindication to intravenous immunoglobulin.
3. Known allergic reactions to blood products, including IVIG and/or subcutaneous immunoglobulin (SCIG), such as history of clinically relevant hemolysis after IVIG infusion, aseptic meningitis, recurrent severe headache, hypersensitivity, severe generalized or severe local skin reactions 
4. Selective IgA deficiency 
5. Current and recent (within five half-lives) use of high-dose corticosteroids (for example, for prior solid organ transplant), omalizumab, anti-TNF-alpha inhibitors
6. Use of immunosuppressants such as Plaquenil or low-dose steroid (prednisone, no more than 10mg a day) will be excluded unless the participant is on stable (>4 weeks) dose 
7. Significant thrombotic events after the acute phase of COVID-19 and/or within six months of enrollment
8. Veins that are not viable for infusions 
9. Not willing to adhere to the dosing schedule for IVIG infusions for nine months    

Ivabradine-Appendix

1. A person of child-bearing potential who is not taking effective contraception 
2. Use of the following medications: clonidine, tizanidine, amphetamines, and serotonin and norepinephrine reuptake inhibitors (SNRIs) with the exception of modafinil 
3. Use of beta-blockers (any formulation), calcium channel blockers, midodrine, pyridostigmine, fludrocortisone, and guanfacine will be excluded unless the participant is on a stable dose (>4 weeks). Participants on stable doses will be allowed to continue the medication throughout the study. 
4. Combination with verapamil or diltiazem, which are moderate CYP3A4 inhibitors with heart rate-reducing properties 
5. Lactating and breast-feeding women 
6. Severe hepatic impairment
7. Use of drugs known to prolong the QT-interval (e.g., quinidine, disopyramide, bepridil, sotalol, amiodarone, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine
8. Concomitant use of digoxin
9. Participants who are pacemaker-dependent 
10. Patients with hypokalemia (serum K+<3.5 mEq/L)
11. Patients taking potassium-depleting diuretics
12. A history of congenital or acquired long QT syndrome, with or without torsade de pointes
13. Patients with high degree AV block, such as Mobitz II

Adult participants who experience autonomic dysfunction symptoms of PASC.

Study Sites

Visit ClinicalTrials.gov to view the updated list of study sites.

Duration of Study Participation

Appendix A =12 months; Appendix B = 6 months

Study Follow-Up

Participants will come for an in-person follow-up visit 3 months after end of interventions.

National Institutes of Health

Visit the RECOVER-AUTONOMIC website for more information.