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

Kanecia Obie Zimmerman

Status and phase: Enrolling; Phase 2

Conditions: Long Covid19; Long Covid-19; Long COVID

Treatments: Drug: Ivabradine Placebo; Behavioral: Coordinated Care; Behavioral: Usual Care; Drug: Ivabradine

Study type: Interventional

Funder types: Other

Identifiers

NCT06305806

Pro00112597_B

OTA-21-015G (Other Grant/Funding Number)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 180 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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 (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

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 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 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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180 participants in 4 patient groups

Ivabradine + Coordinated Care

Experimental group

Description:

The starting dose will be 5 mg twice a day, and the dose will be modified if needed at the 1 month clinic visit. At this visit, HR will be measured and the dose will be modified as applicable. The maximum dose will be 7.5 mg twice daily if HR is ˃ 90 bpm. The table below provides the dosing of ivabradine based on HR. Supine Resting HR 60-80 2.5 mg BID Supine Resting HR \>80 5 mg BID Supine Resting HR \>90 7.5 mg BID \*Resting HR should be measured 5 minutes after lying down

Treatment:

Drug: Ivabradine

Behavioral: Coordinated Care

Ivabradine Placebo + Coordinated Care

Experimental group

Treatment:

Behavioral: Coordinated Care

Drug: Ivabradine Placebo

Ivabradine + Usual Care

Experimental group

Description:

The starting dose will be 5 mg twice a day, and the dose will be modified if needed at the 1 month clinic visit. At this visit, HR will be measured and the dose will be modified as applicable. The maximum dose will be 7.5 mg twice daily if HR is ˃ 90 bpm. The table below provides the dosing of ivabradine based on HR. Supine Resting HR 60-80 2.5 mg BID Supine Resting HR \>80 5 mg BID Supine Resting HR \>90 7.5 mg BID \*Resting HR should be measured 5 minutes after lying down

Treatment:

Drug: Ivabradine

Behavioral: Usual Care

Ivabradine Placebo + Usual Care

Experimental group

Treatment:

Behavioral: Usual Care

Drug: Ivabradine Placebo