IVIG for Post-COVID Syndrome

(RECOVER-AUTO Trial)

Overseen By Orshi Moy

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Duke University

Must not be taking: IVIG, High-dose corticosteroids

Disqualifiers: IVIG allergy, IgA deficiency, 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 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 36 weeks

200 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as high-dose corticosteroids, omalizumab, and anti-TNF-alpha inhibitors, before joining. If you are on immunosuppressants or low-dose steroids, you must be on a stable dose for more than 4 weeks to participate.

What data supports the effectiveness of the drug IVIG for Post-COVID Syndrome?

Research shows that IVIG has been used to treat severe COVID-19 cases, with studies exploring its potential to help with lung injury, immune system overreactions, and severe infections. While its effectiveness for Post-COVID Syndrome specifically isn't clear, its use in severe COVID-19 suggests it might help with related symptoms. ^{1 2 3 4 5}

Is IVIG generally safe for humans?

IVIG is generally considered safe for humans, with most side effects being mild and temporary, such as headaches and abdominal pain. Severe complications are rare and often linked to other risk factors, and careful monitoring can help minimize risks. ^{6 7 8 9 10}

How is the treatment IVIG different from other treatments for post-COVID syndrome?

IVIG (Intravenous Immunoglobulin) is unique because it uses antibodies from donated blood to help regulate the immune system, potentially reducing the overactive immune response seen in severe COVID-19 cases. Unlike other treatments, it can neutralize the suppression of an antibody response against COVID-19 and may offer protection against different virus variants. ^{1 5 11 12 13}

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 Post-Acute Sequelae of SARS-CoV-2 infection (PASC) participants. The interventions tested will include non-pharmacologic care and pharmacologic therapies with study drugs.

Research Team

Peter Novak, MD

Principal Investigator

Harvard

Christopher Grainger, MD

Principal Investigator

Duke Clinical Research Institute

Cyndya Shibao, MD

Principal Investigator

Vanderbilt University Medical Center

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 who have had COVID-19 and are now experiencing autonomic dysfunction symptoms like rapid heartbeat when standing (POTS). Participants must show an abnormal increase in heart rate upon standing, have a specific score on a questionnaire assessing autonomic symptoms (COMPASS-31 > 40), and meet the general criteria listed under NCT########.

Inclusion Criteria

See NCT06305780 for RECOVER-AUTO: Platform Protocol level inclusion criteria which applies to this appendix (or sub-study)

COMPASS-31 Score > 40

My heart races and I feel dizzy or faint when I stand up.

Exclusion Criteria

See NCT06305780 for RECOVER-AUTO: Platform Protocol level exclusion criteria which applies to this appendix (or sub-study)

I have received IVIG treatment before.

My veins cannot be used for infusions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either IVIG or placebo monthly for 9 months to treat autonomic dysfunction symptoms

36 weeks

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• IVIG

Trial Overview The study is testing different treatments for post-COVID complications affecting the nervous system. It includes IVIG (a blood product used to treat immune deficiencies), a placebo version of IVIG, coordinated care involving multiple healthcare providers, and usual care that patients typically receive.

Participant Groups

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

Saline: Same dosage as IVIG; monthly for 9 months (36 weeks)

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

Saline: Same dosage as IVIG; monthly for 9 months (36 weeks)

Group III: IVIG + Usual Care Experimental Treatment 2 Interventions

IVIG (Gamunex); 2g /kg monthly for 9 months (36 weeks)

Group IV: IVIG + Coordinated Care Experimental Treatment 2 Interventions

IVIG (Gamunex); 2g /kg monthly for 9 months (36 weeks)

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

Approved in United States as Intravenous Immunoglobulin for:

• Primary immunodeficiency diseases
• Chronic inflammatory demyelinating polyneuropathy (CIDP)
• Multifocal motor neuropathy
• Kawasaki disease
• Immune thrombocytopenic purpura (ITP)

Approved in European Union as Intravenous Immunoglobulin for:

• Primary immunodeficiency syndromes
• Chronic inflammatory demyelinating polyneuropathy (CIDP)
• Multifocal motor neuropathy
• Kawasaki disease
• Immune thrombocytopenic purpura (ITP)

Approved in Canada as Intravenous Immunoglobulin for:

• Primary immunodeficiency diseases
• Chronic inflammatory demyelinating polyneuropathy (CIDP)
• Multifocal motor neuropathy
• Kawasaki disease
• Immune thrombocytopenic purpura (ITP)

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 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]

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]

In a case series of five patients with COVID-19-related encephalopathy, intravenous immunoglobulin (IVIg) therapy led to complete recovery of neurological symptoms, with initial improvements seen within an average of 3.4 days after treatment began.

IVIg was administered safely, with no adverse events reported, suggesting its potential as an effective treatment due to its anti-inflammatory and anti-cytokine properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous immunoglobulin therapy in COVID-19-related encephalopathy. Muccioli, L., Pensato, U., Bernabè, G., et al.[2021]

In a study of 46 hospitalized adult patients with severe Covid-19, intravenous immunoglobulins (IVIg) were primarily used in complicated cases, showing a 33.7% survival rate as a rescue treatment for those unresponsive to other anti-inflammatory therapies.

Mortality rates were significantly lower in patients receiving IVIg for non-Covid-19 related complications compared to those treated for severe Covid-19 complications, suggesting that the effectiveness of IVIg may vary based on the underlying condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single center experience of intravenous immunoglobulin treatment in Covid-19. Omma, A., Erden, A., Armağan, B., et al.[2022]

Intravenous immunoglobulins (IVIgs) are generally considered safe for treating neuroimmunologic and autoimmune diseases, with severe complications being rare and often linked to preexisting risk factors.

While mild and self-limited side effects can occur, careful screening of patients and monitoring of laboratory parameters can help minimize the risks associated with IVIg therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects of high-dose intravenous immunoglobulins. Stangel, M., Hartung, HP., Marx, P., et al.[2019]

In a study of 305 intravenous immunoglobulin G (IVIG) infusions given to 111 pediatric patients, only 3.9% of infusions resulted in adverse reactions, indicating a low incidence of side effects in this population.

The most severe adverse reactions included two cases of aseptic meningitis and one case of seizures, all of which resolved completely, suggesting that while IVIG is generally safe, monitoring for rare severe reactions is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous immunoglobulin G use and pharmacovigilance in a tertiary care children's hospital. Yori, S., Belleri, F., Testard, J., et al.[2021]

A study of 345 pediatric patients receiving intravenous immunoglobulin (IVIG) at Hamad General Hospital found that IVIG has a good safety profile, with low incidence of severe adverse drug reactions (ADRs) such as fever (5.8%) and chills (2.6%).

The only significant factor associated with the occurrence of ADRs was the specific brand of IVIG used, indicating that different formulations may have varying safety profiles, and further research is needed to explore this relationship.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of intravenous immunoglobulin in pediatric patients: a retrospective, 1-year observational study. Elajez, R., Ezzeldin, A., Gaber, H.[2022]

Adverse reactions (ARs) to intravenous immunoglobulin (IVIG) therapy occurred in 4.9% of patients and 2.5% of infusions, with most reactions being mild and transient.

Significant risk factors for ARs included being female, having neuromuscular disease, and receiving higher doses of IVIG per body weight, indicating that certain patient demographics and conditions may increase the likelihood of experiencing ARs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Retrospective Observational Study of Adverse Reactions Associated With Intravenous Immunoglobulin Infusion. Kato, H., Hayashi, M., Ohashi, W., et al.[2023]

In a 2-year study involving 117 patients with primary immunodeficiency diseases receiving regular intravenous immunoglobulin (IVIG) therapy, only 2.15% of infusions resulted in immediate adverse reactions, indicating that IVIG is generally safe.

The most common mild reactions included malaise, headache, and abdominal pain, with severe reactions being rare; however, the risk of adverse reactions was higher with the drug Tegeline® compared to Octagam®.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immediate infusion-related adverse reactions to intravenous immunoglobulin in a prospective cohort of 1765 infusions. Bichuetti-Silva, DC., Furlan, FP., Nobre, FA., et al.[2022]

Human intravenous immunoglobulin (IVIG) preparations contain IgG antibodies that can inhibit the entry of SARS-CoV-2 pseudovirus into host cells by approximately 40%, even at low concentrations, suggesting potential therapeutic benefits for COVID-19.

The study indicates that IVIG may be effective against various SARS-CoV-2 variants due to its ability to bind to both the virus's spike proteins and human ACE2/TMPRSS2, highlighting its role in COVID-19 treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-Reactivity of Antibodies in Intravenous Immunoglobulin Preparation for Protection against SARS-CoV-2. Osaka, T., Yamamoto, Y., Soma, T., et al.[2023]

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]

Intravenous immunoglobulin (IvIg) therapy may help reduce severe COVID-19 disease by counteracting the immune system's overreaction, known as a cytokine storm, which causes damage to multiple organs.

IvIg contains a balanced network of natural antibodies that can neutralize suppressor memory B cells, potentially restoring a proper immune response against SARS-CoV-2 and suggesting its use in treating autoimmune diseases as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How IvIg Can Mitigate Covid-19 Disease: A Symmetrical Immune Network Model. Kohler, H., Kaveri, S.[2022]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

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

3. Netherlands pubmed.ncbi.nlm.nih.gov

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

4. Germany pubmed.ncbi.nlm.nih.gov

Intravenous immunoglobulin therapy in COVID-19-related encephalopathy. [2021]

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

A single center experience of intravenous immunoglobulin treatment in Covid-19. [2022]

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

Side effects of high-dose intravenous immunoglobulins. [2019]

7. Argentina pubmed.ncbi.nlm.nih.gov

Intravenous immunoglobulin G use and pharmacovigilance in a tertiary care children's hospital. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of intravenous immunoglobulin in pediatric patients: a retrospective, 1-year observational study. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

A Retrospective Observational Study of Adverse Reactions Associated With Intravenous Immunoglobulin Infusion. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Immediate infusion-related adverse reactions to intravenous immunoglobulin in a prospective cohort of 1765 infusions. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Cross-Reactivity of Antibodies in Intravenous Immunoglobulin Preparation for Protection against SARS-CoV-2. [2023]

12. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

How IvIg Can Mitigate Covid-19 Disease: A Symmetrical Immune Network Model. [2022]