Ivabradine and IVIG for Long COVID Syndrome

(RECOVER-AUTO Trial)

Recruiting at 64 trial locations

Overseen By Barrie L Harper, BSMT (ASCP) PMP

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Duke University

Disqualifiers: Pregnancy, Renal failure, Atrial fibrillation, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 9 months (IVIG) or 3 months (Ivabradine)

380 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Ivabradine and IVIG for Long COVID Syndrome?

Research shows that Intravenous Immunoglobulin (IVIG) has been used to help treat severe COVID-19 cases by managing infections and reducing complications like lung injury and inflammation. While this doesn't directly prove its effectiveness for Long COVID, it suggests potential benefits in managing related symptoms. ^{1 2 3 4 5}

How is the drug Ivabradine unique in treating Long COVID Syndrome?

Ivabradine is unique because it specifically lowers heart rate by targeting the heart's natural pacemaker without affecting other heart functions, and it also has additional benefits like reducing inflammation and improving heart health, which may help with cardiovascular issues related to Long COVID. ^{6 7 8 9 10}

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

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

Christopher Granger, MD

Principal Investigator

Duke Clinical Research Institute

Tae Chung, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

Adults over 18 with long COVID symptoms like fever, cough, fatigue, and more for at least 12 weeks post-infection. Participants must have had a confirmed or suspected case of COVID-19 before May 1, 2021. Severe autonomic dysfunction patients are excluded.

Inclusion Criteria

I have tested positive for COVID-19 or meet the criteria for it.

OHQ/OIQ, question 1 score >2

I have had COVID-19 before, as confirmed by a health organization.

Exclusion Criteria

I have a history of serious blood clotting disorders.

My kidney function is very low (eGFR below 20).

Known pregnancy, breast-feeding, or contemplating pregnancy during the study period

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either IVIG or placebo for 9 months or ivabradine or placebo for 3 months, along with coordinated or usual non-pharmacologic care

9 months (IVIG) or 3 months (Ivabradine)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Ivabradine
• IVIG

Trial Overview The trial is testing the effectiveness of Ivabradine and IVIG (an immune therapy) against placebos in managing long COVID symptoms related to the nervous system. It includes usual care and coordinated care approaches in different combinations.

Participant Groups

Group I: Ivabradine Experimental Treatment 4 Interventions

In the ivabradine study, randomization will be implemented with 1:1:1:1 allocation among the combinations of ivabradine/placebo and coordinated/usual care. All participants receive either ivabradine or placebo for 3 months (12 weeks) with a follow-up period for an additional 3 months (total study duration of 6 months). See NCT06305806 for additional details.

Group II: IVIG Experimental Treatment 4 Interventions

In the IVIG study, randomization will be implemented with 1:1:1:1 allocation among the combination of IVIG/placebo and coordinated/ usual non-pharmacologic care. All participants will receive IVIG or placebo for 9 months (36 weeks) with a follow-up period for an additional 3 months (total study duration for 12 months). See NCT06305793 for additional details.

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

In a study of 850 severe COVID-19 patients, IVIG treatment did not significantly reduce 28-day mortality compared to untreated patients, suggesting limited efficacy in this context.

The study found no major differences in other serious complications between IVIG-treated and untreated patients, except for a slight advantage in the use of prone position ventilation in the IVIG group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous immunoglobulin treatment for patients with severe COVID-19: a retrospective multicentre study. Liu, J., Chen, Y., Li, R., et al.[2022]

Intravenous Immunoglobulin (IVIG) therapy has shown clinical efficacy in reducing mortality for critically ill COVID-19 patients, based on a meta-analysis of 7 studies involving 825 hospitalized patients.

However, IVIG did not demonstrate significant benefits for patients with severe or non-severe COVID-19, indicating that its effectiveness may be closely linked to the severity of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of IVIG (intravenous immunoglobulin) for corona virus disease 2019 (COVID-19): A meta-analysis. Xiang, HR., Cheng, X., Li, Y., et al.[2022]

Intravenous immunoglobulin (IVIg) therapy may be beneficial for certain COVID-19 patients, particularly those in the late phase of the disease or those experiencing sepsis due to bacterial superinfection, as identified by a panel of experts.

The panel found the rationale for using IVIg in the early phase of COVID-19 to be uncertain, highlighting the need for ongoing trials to determine the most effective use of this therapy in managing severe COVID-19 cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale for Polyclonal Intravenous Immunoglobulin Adjunctive Therapy in COVID-19 Patients: Report of a Structured Multidisciplinary Consensus. Coloretti, I., Berlot, G., Busani, S., et al.[2021]

In a phase I/II trial involving 50 severely and critically ill COVID-19 patients, the use of hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG) significantly reduced mortality rates compared to standard care, with only 25% mortality in the intervention group versus 60% in the control group.

C-IVIG treatment also improved clinical outcomes, as evidenced by significant enhancements in the Horowitz index and clinical status, with no reported adverse events, indicating it is a safe and effective therapy for severe COVID-19 cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: A phase I/II randomized control trial. Ali, S., Uddin, SM., Shalim, E., et al.[2022]

Intravenous immunoglobulin (IVIG) is a therapy commonly used to help patients with immune deficiencies and autoimmune conditions, and it may also be beneficial for treating severe COVID-19 cases.

This report presents a case where IVIG was administered to a patient with COVID-19, suggesting its potential role in managing severe infections caused by SARS-CoV-2, although specific treatments for COVID-19 are still being researched.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of a case of COVID-19 by intravenous immunoglobulin. Çolak, M., Kalemci, S., Sarıhan, A.[2022]

Procoralan (Ivabradine) effectively reduces heart rate by specifically inhibiting the If current, which can help prevent myocardial ischemia during rest and exercise.

It is particularly useful for treating chronic stable angina pectoris in patients who cannot tolerate or are contraindicated for beta-blockers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ivabradine--a medical alternative for patients with chronic stable angina pectoris]. Haghfelt, TH.[2018]

Ivabradine effectively lowers heart rate by specifically inhibiting the funny current in the sinus node, making it a targeted treatment for adults with chronic heart failure and a resting heart rate of ≥75 bpm.

In the SHIFT study involving over 6,500 participants, ivabradine significantly reduced the risk of cardiovascular death or hospital admission for worsening heart failure by 18% compared to placebo, although it was associated with a higher rate of treatment discontinuation due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivabradine: in adults with chronic heart failure with reduced left ventricular ejection fraction. Perry, CM.[2018]

Acute cardiac injury is a significant complication of severe COVID-19, leading to poor outcomes, and is often exacerbated by systemic inflammation that increases heart rate and disrupts cardiac function.

Ivabradine, a drug that selectively lowers heart rate without negatively affecting heart contractility, may offer protective benefits against cardiovascular issues related to COVID-19, including myocarditis and acute coronary syndrome, due to its various beneficial effects beyond just heart rate reduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivabradine in the Management of COVID-19-related Cardiovascular Complications: A Perspective. Baka, T., Repova, K., Luptak, I., et al.[2022]

In a study of 2,330 patients with stable angina pectoris, adding ivabradine to beta-blocker therapy significantly reduced heart rate by an average of 19.4 beats per minute and decreased the number of angina attacks by 1.4 per week over 4 months.

Patients reported improved quality of life, with most moving from a higher angina severity classification (CCS grade II) to a lower one (CCS grade I), and physicians rated the overall efficacy of ivabradine as 'very good' or 'good' in 97% of cases, with minimal adverse reactions reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivabradine in combination with beta-blocker improves symptoms and quality of life in patients with stable angina pectoris: results from the ADDITIONS study. Werdan, K., Ebelt, H., Nuding, S., et al.[2021]

In a study of 72 patients with coronary artery disease and left ventricular dysfunction, Ivabradine (Coraxan) combined with standard therapy significantly reduced heart rate and improved heart function compared to Nebivolol (Nebilet) over a 6-month period.

The combination of Ivabradine with standard therapy led to better anti-ischemic effects and a greater improvement in congestive heart failure symptoms than the combination of Nebivolol with standard therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical-hemodynamic and anti-ischemic effects ivabradine and nebivolol ischemic heart disease with left ventricular dysfunction]. Abuladze, GV., Kvirkveliia, AA., Nebieridze, MI., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Intravenous immunoglobulin treatment for patients with severe COVID-19: a retrospective multicentre study. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy of IVIG (intravenous immunoglobulin) for corona virus disease 2019 (COVID-19): A meta-analysis. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Rationale for Polyclonal Intravenous Immunoglobulin Adjunctive Therapy in COVID-19 Patients: Report of a Structured Multidisciplinary Consensus. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: A phase I/II randomized control trial. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of a case of COVID-19 by intravenous immunoglobulin. [2022]

6. Denmark pubmed.ncbi.nlm.nih.gov

[Ivabradine--a medical alternative for patients with chronic stable angina pectoris]. [2018]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Ivabradine: in adults with chronic heart failure with reduced left ventricular ejection fraction. [2018]

8. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Ivabradine in the Management of COVID-19-related Cardiovascular Complications: A Perspective. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Ivabradine in combination with beta-blocker improves symptoms and quality of life in patients with stable angina pectoris: results from the ADDITIONS study. [2021]

10. Georgia (Republic) pubmed.ncbi.nlm.nih.gov

[Clinical-hemodynamic and anti-ischemic effects ivabradine and nebivolol ischemic heart disease with left ventricular dysfunction]. [2018]