Ivabradine for Long-Term Effects of COVID-19 With POTS Cohort

The purpose of the study is three-fold. The primary aim is to identify the proportion of Long-Haul COVID (LHC) and non-LHC volunteers with relevant symptoms actually have postural orthostatic tachycardia syndrome (POTS). The second is to determine benefit of ivabradine treatment. Ivabradine is a drug approved to treat tachycardia in persons with heart failure. The third is to characterize risk factors and outcomes among volunteers with and without LHC. This will include comparison with COVID-19-positive individuals who did not develop long-COVID symptoms.

The study will improve basic and applied knowledge of LHC and its associated cardiovascular and autonomic consequences. Cellular and molecular characterization of LHC and non-LHC participants will be performed with a nested clinical trial for Ivabradine responsiveness on reduction of tachycardia. It is hoped that a greater understanding of LHC, and related autonomic dysfunction in particular will help to identify treatment paradigms and therapeutic targets for improving recovery and enhancing health for those affected.

The study will first attempt to address the frequency of clinically confirmed POTS in those with persistent COVID-19 symptoms, particularly those symptoms suggestive of autonomic dysfunction.

Those with confirmed POTS or Inappropriate sinus tachycardia (IST) will be randomized to ivabradine or placebo to determine efficacy in reducing heart rate as a putative surrogate for POTS disease as well as effects on POTS symptoms. The biopsychosocial mechanisms of LHC and POTS will also be explored. Specific objectives will be:

1. To assess the frequency and severity of fatigue, dyspnea, headache, and confusion and other suggestive symptoms among volunteers with and without LHC and measure the occurrence of clinically confirmed POTS or IST-in relation to these symptoms.
2. To assess whether treatment with ivabradine will significantly reduce heart rate and improve symptoms and quality of life among subjects manifesting typical POTS or similar autonomic dysregulation.
3. To characterize the immunoinflammatory and genomic factors associated with LHC and POTS among those with LHC. In particular, to determine whether those with POTS have differential expression of genes and/or proteins associated with autonomic nervous system function. To determine whether these factors reflect a genetic predisposition.
4. To determine whether wearable automated ambulatory monitoring with existing FDA-approved devices will permit improved diagnostic accuracy for POTS.
5. To determine the degree to which LHC induced autonomic instability and whether it is associated with induced inflammation and/or dysregulation
6. To evaluate potential contribution of psychological symptoms and the interplay between psychosocial symptoms, quality of life, cognitive symptoms, and physiologic responses induced by LHC.
7. To determine whether LHC improves following vaccination (in the limited number of cases where late vaccination occurs) and/or "breakthrough" clinical COVID-19 infection.
8. Assess whether individuals with LHC have different antibody and/or cellular immune responses to SARS-CoV-2 antigens compared to infected individuals who did not develop LHC.
9. Assess whether specific plasma protein markers of dysregulated blood coagulation, which were significantly correlated with immunothrombosis in severe COVID-19, persist in individuals with LHC.

Eligibility Criteria:
Inclusion Criteria:

1. Age 18-80
2. History of documented COVID-19 infection of any severity to include a positive COVID-19 PCR, or antibody test
3. Meets criteria for 'long-haul' COVID-19 with symptoms \>12 weeks following acute illness
4. Able and willing to provide informed consent and participate for study duration
5. Willing to participate in the nested randomized controlled trial of ivabradine if RCT enrollment criteria are met
6. Access to a primary healthcare provider and proof of health insurance

Inclusion Criteria for non-LHC Cohort

1. Age 18-80
2. History of documented COVID-19 infection of any severity to include a positive COVID-19 PCR, or antibody test
3. Does not meet criteria for 'long-haul' COVID-19
4. Able and willing to provide informed consent and participate for study duration
5. Willing to participate in the nested randomized controlled trial of ivabradine if RCT enrollment criteria are met
6. Access to a primary healthcare provider and proof of health insurance

Inclusion Criteria for POTS RCT:

1. Age 18-80; Meets criteria for 'long-haul' COVID-19

   1. Documented history of COVID-19 infection made available to study team 1914
   2. Lack of documented history, but evidence of infection from sensitive antibody tests
2. Able and willing to provide informed consent and participate for study duration
3. Volunteers with or without LHC combined with POTS based on an increase in comparing the supine heart rate to standing heart rate \>20 beats per minute with a drop in systolic blood pressure less than 20 mm Hg or a drop in diastolic blood pressure less than 10 mm Hg will be included, OR additionally, volunteers with or without LHC and a 24-hour mean heart rate of 90 beats per minute or more (in sinus rhythm) will be diagnosed with IST and be included.
4. For females of childbearing age - willing to use a highly effective form of contraceptive with \<1% failure rate or practice abstinence for the duration of the study

Exclusion Criteria:

1. Resting heart rate \<60 bpm
2. Atrial fibrillation
3. Supraventricular tachycardia
4. Allergic reaction or known contraindications to study drug

   1. Acute decompensated heart failure
   2. Clinically significant hypotension, defined as a drop in systolic BP \>20 mmHg or drop in diastolic \>10 mmHg during orthostatic vital signs testing.
   3. Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand pacemaker is present
   4. Clinically significant bradycardia
   5. Severe hepatic impairment
   6. Pacemaker dependence (heart rate maintained exclusively by the pacemaker)
   7. Concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors or inducers
5. Pregnant/lactating females
6. Impaired gastrointestinal absorption that would preclude oral drug administration
7. Taking any of the following without discontinuation in consultation with the volunteer's healthcare provider and a one-week washout period:

   1. ivabradine
   2. beta-blockers
   3. calcium- channel blockers
   4. cholinesterase inhibitors (pyridostigmine),
   5. vasoconstrictors (midodrine, octreotide, droxidopa, stimulants)
   6. sympatholytics (clonidine, methyldopa)
   7. blood volume enhancers (fludrocortisone, desmopressin, salt supplementation)
   8. oral ketoconazole (contraindicated)
8. Acute suicidality identified at screening

   -