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

NCT06305806 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: Pro00112597_BOTA-21-015G
• Study Type: interventional
• Target: 181
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Long COVID; Long Covid-19

Keywords

PASC; POTS

Outcome Measures

Primary Outcomes (1)

• 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.

  Baseline to End of Intervention (3 months)

Secondary Outcomes (6)

• Change in Composite Autonomic Symptoms Score 31 (COMPASS-31)

  Baseline to End of Intervention (3 months)

• Change in Malmo POTS Symptom Score

  Baseline to End of Intervention (3 months)

• Change in heart rate (HR)

  Baseline to End of Intervention (3 months)

• Change in 6-min Walk Test

  Baseline to End of Intervention (3 months)

• Change in PROMIS-29 + 2 Questionnaire

  Baseline to End of Intervention (3 months)

Study Arms (4)

Ivabradine + Coordinated Care

EXPERIMENTAL

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

Drug: Ivabradine; Behavioral: Coordinated Care

Ivabradine Placebo + Coordinated Care

EXPERIMENTAL

Drug: Ivabradine Placebo; Behavioral: Coordinated Care

Ivabradine + Usual Care

EXPERIMENTAL

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

Drug: Ivabradine; Behavioral: Usual Care

Ivabradine Placebo + Usual Care

EXPERIMENTAL

Drug: Ivabradine Placebo; Behavioral: Usual Care

Interventions

Ivabradine DRUG

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 + Coordinated Care; Ivabradine + Usual Care

Ivabradine Placebo DRUG

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).

Ivabradine Placebo + Coordinated Care; Ivabradine Placebo + Usual Care

Coordinated Care BEHAVIORAL

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.

Ivabradine + Coordinated Care; Ivabradine Placebo + Coordinated Care

Usual Care BEHAVIORAL

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

Ivabradine + Usual Care; Ivabradine Placebo + Usual Care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Kanecia Obie Zimmerman: lead

Study Sites (1)

All sites listed under NCT06305780

Durham, North Carolina, 27710, United States

Location

Related Publications (1)

• Fudim M, Novak P, Taub PR, Chung T, Zimmerman KO, Moy OV, Fissler HZ, Wen J, Freeman NLB, O'Brien S, Marti H, Cook D, Low P, Kim DY, Rosenberg Y, Granger CB, Shibao CA. Design and rationale of RECOVER-AUTONOMIC: A randomized platform trial evaluating interventions for Long COVID postural orthostatic tachycardia syndrome. Am Heart J. 2026 Jun;296:107384. doi: 10.1016/j.ahj.2026.107384. Epub 2026 Feb 18.

  PMID: 41720282 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Post-Acute COVID-19 Syndrome

Interventions

Ivabradine

Condition Hierarchy (Ancestors)

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Post-Infectious Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Christopher Grainger, MD

  Duke Clinical Research Institute

  STUDY CHAIR

• Cyndya Shibao, MD

  Vanderbilt University Medical Center

  STUDY CHAIR

• Peter Novak, MD

  Harvard

  STUDY CHAIR

• Pam Taub, MD

  University of California, San Diego

  STUDY CHAIR

• Tae Chung, MD

  Johns Hopkins University

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Double blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Model Details: In each Appendix trial, each participant will be assigned with equal probability to one of the factorial combinations based on two factors: (1) a study intervention/control and (2) non-pharmacologic intervention/control if the participant is eligible for the study intervention.

Study Record Dates

• First Submitted: March 4, 2024
• First Posted: March 12, 2024
• Study Start: March 11, 2024
• Primary Completion: October 13, 2025
• Study Completion: December 17, 2025
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)