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

Kanecia Obie Zimmerman181 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

181

Conditions

Long COVID Long Covid19 Long Covid-19

Interventions

IvabradineDRUG

Participants will receive ivabradine for 3 months (12 weeks) with a follow-up period for an additional 3 months (total study duration of 6 months).

Ivabradine PlaceboDRUG

The control (placebo) oral tablets will be similar to the study drug, ivabradine. The control packaging matches the packaging. Participants will receive placebo for 3 months (12 weeks) with a follow-up period for an additional 3 months (total study duration of 6 months).

Coordinated CareBEHAVIORAL

Participants will receive 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.

Usual CareBEHAVIORAL

Participants will receive usual non-pharmacologic care (control) for a duration of 3 months, concurrent with ivabradine administration.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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: 1\. 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: 1. A person of child-bearing potential who is not taking effective contraception 2. 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 3. Combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate reducing properties 4. Severe hepatic impairment 5. 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 6. Concomitant use of digoxin or Paxlovid 7. Known history of atrial fibrillation or significant cardiac arrhythmia not due to reversible cause 8. Participants who are pacemaker dependent 9. Patients with hypokalemia (serum K+\<3.5 mEq/L) 10. 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. 11. A history of congenital or acquired long QT syndrome, with or without torsade de pointes 12. Patients with high degree AV block such as Type 2 AV block, Mobitz II

Outcomes

Primary Outcomes

Change in Orthostatic Hypotension Questionnaire (OHQ)/Orthostatic Intolerance Questionnaire (OIQ) Composite Score

The OHQ / OIQ is a measure of orthostatic intolerance and includes a 6-item symptom assessment (OHSA) and the 4-item Daily Activity Scale (OHDAS). Each item is scored from 0 (none/no interference) to 10 (worst possible/complete interference), describing the preceding week. The OHSA composite score is the average of the first 6 non-zero items and the OHDAS composite score is the average of the last 4 non-zero items. The OHQ/OIQ composite score is the average of the OHSA and OHDAS composite scores. The OHQ/OIQ scales at post-baseline are calculated using only those items that were included in the baseline scores.