Ivabradine for Long COVID Syndrome

(RECOVER-AUTO Trial)

Recruiting at 1 trial location

Overseen By Barrie L Harper, BSMT(ASCP)PMP

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Duke University

Must not be taking: Clonidine, Amphetamines, SNRIs, others

Disqualifiers: Pregnancy, Lactation, Hepatic impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 3 months

180 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

You may need to stop taking certain medications like clonidine, tizanidine, amphetamines, and some antidepressants, unless you are on a stable dose of specific drugs like beta-blockers or calcium channel blockers. It's best to discuss your current medications with the trial team to see if any changes are needed.

How does the drug Ivabradine differ from other treatments for long COVID?

Ivabradine is unique because it specifically targets and reduces heart rate by inhibiting the 'funny' current (a specific electrical current in the heart), which may help alleviate cardiovascular symptoms like high heart rate and palpitations in long COVID, unlike other treatments that do not directly address these symptoms. ^{1 2 3 4 5}

What is the purpose of this trial?

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.

Research Team

Christopher Grainger, MD

Principal Investigator

Duke Clinical Research Institute

Cyndya Shibao, MD

Principal Investigator

Vanderbilt University Medical Center

Peter Novak, MD

Principal Investigator

Harvard

Pam Taub, MD

Principal Investigator

University of California, San Diego

Tae Chung, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

This trial is for individuals with long-term symptoms after COVID-19, known as Long COVID or PASC, who experience rapid heart rate upon standing (orthostatic tachycardia) and related symptoms. Participants should have a specific score on a questionnaire assessing autonomic dysfunction and not be enrolled in certain other sub-studies.

Inclusion Criteria

I feel dizzy and my heart races when I stand up.

COMPASS-31 Score > 25 and not enrolled in the IVIG appendix

Exclusion Criteria

I have severe liver problems.

I am taking verapamil or diltiazem.

Lactating and breast-feeding women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Ivabradine or placebo with usual or coordinated care. The starting dose is 5 mg twice a day, adjusted at the 1-month clinic visit based on heart rate.

3 months

1 visit (in-person) at 1 month for dose adjustment

Follow-up

Participants are monitored for safety and effectiveness after treatment, including incidence of SAEs and ESIs.

6 months

Treatment Details

Interventions

• Ivabradine

Trial Overview The study compares the effects of Ivabradine, a heart rate reducing medication, against a placebo. It also evaluates coordinated care versus usual healthcare practices to manage post-COVID autonomic dysfunction including cardiovascular issues and POTS.

Participant Groups

Group I: Ivabradine Placebo + Usual Care Experimental Treatment 2 Interventions

Group II: Ivabradine Placebo + Coordinated Care Experimental Treatment 2 Interventions

Group III: Ivabradine + Usual Care Experimental Treatment 2 Interventions

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

Group IV: Ivabradine + Coordinated Care Experimental Treatment 2 Interventions

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

Ivabradine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Corlanor for:

• Heart failure
• Angina

Approved in European Union as Procoralan for:

• Angina
• Heart failure

Approved in Canada as Lancora for:

• Angina
• Heart failure

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Kanecia Obie Zimmerman

Lead Sponsor

Trials

9

Recruited

3,300+

Findings from Research

Many COVID-19 survivors experience long-lasting cardiovascular issues, such as fatigue and arrhythmias, due to autonomic nervous system dysfunction, highlighting the need for effective management strategies for long-COVID.

Cardiovascular rehabilitation programs (CRPs) have shown promise in improving heart health and reducing risks in patients with cardiovascular diseases, suggesting they could be beneficial for treating the cardiovascular effects of long-COVID.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular and autonomic dysfunction in long-COVID syndrome and the potential role of non-invasive therapeutic strategies on cardiovascular outcomes. Allendes, FJ., Díaz, HS., Ortiz, FC., et al.[2023]

In a study of 14 patients with long-COVID symptoms linked to mast cell activation, treatment with histamine receptor blockers (fexofenadine and famotidine) led to complete symptom resolution in 29% of patients after 20 days.

All treated patients showed significant improvement in symptoms like fatigue and increased heart rate compared to a control group, suggesting that targeting mast cell activation may be an effective approach for managing long-COVID.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation. Salvucci, F., Codella, R., Coppola, A., et al.[2023]

Long-COVID syndrome is a complex condition that can affect multiple organs and persists for more than 12 weeks after a COVID-19 infection, with significant involvement of the neuro-cardiology system due to factors like inflammation and oxidative stress.

Therapies targeting autonomic dysfunction, chronic inflammation, and oxidative stress are recommended to alleviate symptoms, alongside comprehensive assessments of the autonomic nervous system and cardiac health to differentiate between cardiac and neural causes of symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-COVID Syndrome and the Cardiovascular System: A Review of Neurocardiologic Effects on Multiple Systems. DePace, NL., Colombo, J.[2023]

Long COVID, or post-acute COVID-19 syndrome, affects many patients even after hospital discharge, leading to a range of symptoms including cardiorespiratory issues and psychological disturbances, which significantly impact their quality of life.

The review highlights that Long COVID may act as a new cardiovascular risk factor, potentially altering the prognosis of patients and necessitating further research and specialized management through Long COVID clinics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unmasking Pandemic Echoes: An In-Depth Review of Long COVID's Unabated Cardiovascular Consequences beyond 2020. Luchian, ML., Higny, J., Benoit, M., et al.[2023]

Outpatient treatment with metformin significantly reduced the incidence of long COVID by about 41%, with a cumulative incidence of 6.3% in those treated with metformin compared to 10.4% in the placebo group, based on a study involving 1,126 participants followed for at least 9 months.

Neither ivermectin nor fluvoxamine showed any significant effect on the incidence of long COVID, highlighting metformin's unique potential as a safe and effective treatment option for reducing long COVID risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial. Bramante, CT., Buse, JB., Liebovitz, DM., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Cardiovascular and autonomic dysfunction in long-COVID syndrome and the potential role of non-invasive therapeutic strategies on cardiovascular outcomes. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Long-COVID Syndrome and the Cardiovascular System: A Review of Neurocardiologic Effects on Multiple Systems. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Unmasking Pandemic Echoes: An In-Depth Review of Long COVID's Unabated Cardiovascular Consequences beyond 2020. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial. [2023]