RECOVER-AUTONOMIC: Platform Protocol, Appendix B (Ivabradine)

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.

Inclusion criteria

• See NCT06305780 for RECOVER-AUTO: Platform Protocol level inclusion criteria which applies to this appendix (or sub-study)

Additional Appendix B (Ivabradine Sub-study) Level Inclusion Criteria:

• Abnormal active standing test defined as presence of orthostatic tachycardia and experiencing orthostatic symptoms. Orthostatic tachycardia defined as: Increase of 30 beats per minute (bpm) or more in HR within 10 minutes upon standing without orthostatic hypotension (decline of ≥ 20 mmHg of systolic or ≥ 10 mmHg of diastolic blood pressure after 3 minutes of standing) OR History of documented increase of 30 bpm or more from an active stand test or tilt table test without orthostatic hypotension in the past 1 year AND standing HR above 100 bpm at the Screening/Baseline visit active stand test.

Exclusions Criteria:

• See NCT06305780 for RECOVER-AUTO: Platform Protocol level inclusion criteria which applies to this appendix (or sub-study)

Additional Appendix B (Ivabradine Sub-study) Level Exclusion Criteria:

• A person of child-bearing potential who is not taking effective contraception
• Use of midodrine, pyridostigmine, fludrocortisone, and guanfacine will be excluded unless participant is on a stable dose (>4 weeks). Participants on stable doses will be allowed to continue the medication throughout the study
• Combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate reducing properties
• Severe hepatic impairment
• Use of drugs known to prolong the QT-interval (e.g., quinidine, disopyramide, bepridil, sotalol, amiodarone, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidineUse of drugs known to prolong the QT-interval (e.g., quinidine, disopyramide, bepridil, sotalol, amiodarone, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine
• Concomitant use of digoxin or Paxlovid
• Known history of atrial fibrillation or significant cardiac arrhythmia not due to reversible cause
• Participants who are pacemaker dependent
• Patients with hypokalemia (serum K+<3.5 mEq/L)
• Patients taking potassium-depleting diuretics, unless potassium level is normal at the baseline CMP, in which case participants may continue taking it during the study.
• A history of congenital or acquired long QT syndrome, with or without torsade de pointes
• Patients with high degree AV block such as Type 2 AV block, Mobitz II