Ivabradine for Long COVID Syndrome

(RECOVER-AUTO Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests ivabradine (also known as Corlanor, Procoralan, and other names) to determine its effectiveness in treating Long COVID symptoms, particularly heart-related issues like a fast heartbeat when standing (known as POTS). Participants will receive either ivabradine or a placebo, alongside their regular care, to assess the drug's effectiveness. The trial suits individuals experiencing symptoms such as a fast heartbeat or dizziness when standing. Participants should not be taking certain medications or have specific health conditions, such as severe liver problems or pacemaker dependency. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ivabradine is generally safe for use. It helps manage heart rate problems and conditions like POTS, which affects blood flow and can cause dizziness and fainting, especially in individuals with long COVID. Other studies have used ivabradine to control heart rate without causing serious side effects.

While all medications can have some side effects, ivabradine's most common ones are usually mild. These may include changes in vision, such as seeing bright spots, or a slower heart rate. Prospective trial participants should discuss any concerns with the study team, who can provide detailed information based on current research. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike the standard of care for Long COVID, which typically includes symptom management through medications like beta-blockers and lifestyle changes, Ivabradine works uniquely by specifically targeting and slowing the heart rate. This is particularly promising for Long COVID patients who suffer from symptoms like fatigue and tachycardia, as Ivabradine may address these issues directly by modulating heart rate without affecting blood pressure. Researchers are excited about this treatment because it offers a targeted approach that could improve quality of life for patients who haven't found relief with existing options.

What evidence suggests that this trial's treatments could be effective for Long COVID Syndrome?

Research shows that ivabradine can help manage heart rate issues in people with long COVID, particularly those with postural orthostatic tachycardia syndrome (POTS). POTS occurs when the heart rate significantly increases upon standing. Studies have found that ivabradine can control these heart rate problems by slowing the heart, potentially reducing symptoms like tiredness and dizziness. In this trial, participants will receive either ivabradine or a placebo, combined with either usual care or coordinated care. Early findings suggest ivabradine might benefit those with heart-related symptoms from long COVID. While more research continues, these early results are promising for managing some symptoms of long COVID. ^{1 2 5 6 7}

Who Is on the Research Team?

Peter Novak, MD

Principal Investigator

Harvard

Pam Taub, MD

Principal Investigator

University of California, San Diego

Tae Chung, MD

Principal Investigator

Johns Hopkins University

Christopher Grainger, MD

Principal Investigator

Duke Clinical Research Institute

Cyndya Shibao, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12278775/

Comparative cohort study of post-acute COVID-19 infection ... In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05481177)%C3%BCber

Ivabradine for Long-Term Effects of COVID-19 With POTS ... The study will first attempt to address the frequency of clinically confirmed POTS in those with persistent COVID-19 symptoms, particularly those symptoms ...

3. researchgate.net researchgate.net/publication/393484434_Comparative_cohort_study_of_post-acute_COVID-19_infection_with_a_nested_randomized_controlled_trial_of_ivabradine_for_those_with_postural_orthostatic_tachycardia_syndrome_the_COVIVA_study

Comparative cohort study of post-acute COVID-19 infection ... In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2667036424000086

A System-wise Approach on the Effects of Long-Covid-19 PASC can manifest with a wide range of symptoms, including fatigue, dyspnea, cognitive dysfunction, chest pain, headache, muscle aches, joint pain, insomnia, ...

5. academic.oup.com academic.oup.com/eurheartj/article/43/11/1157/6529562

post-acute sequelae of COVID-19 with a cardiovascular focus In this review, we discuss the definition of long COVID, epidemiology of cardiopulmonary manifestations in the context of long COVID, ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0092867424008869

Mechanisms of long COVID and the path toward therapeutics Long COVID is defined as a “chronic disease state” that may be clinically diagnosed after 3 months of symptoms or diagnosable conditions that affect one or ...

7. trials.recovercovid.org trials.recovercovid.org/documents/RECOVER_AUTONOMIC_Protocol_V3.0.pdf

RECOVER-AUTONOMIC: A Platform Protocol for ... RECOVER-AUTONOMIC: A Platform Protocol for. Evaluation of Interventions for Autonomic Dysfunction in Post-Acute Sequelae of SARS-CoV-2 ...