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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called IVIG, or intravenous immunoglobulin, to determine its effectiveness for post-COVID symptoms such as heart issues or dizziness when standing. The trial compares IVIG with standard care options, including non-drug treatments, to identify the best approach for managing these symptoms. Participants who experience a rapid heartbeat when standing and have related symptoms might be suitable for this trial. 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?

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.

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

Research has shown that IVIG (intravenous immunoglobulin) is generally safe. Studies have found it helpful in treating COVID-19-related nerve and brain issues, with patients experiencing few side effects. One study found that IVIG helped remove the virus in people with weak immune systems, suggesting its safety in different COVID-19 situations. Importantly, the FDA has already approved IVIG for other uses, which adds to its safety profile. While side effects can occur, they are usually mild, such as headaches or fever. Overall, the safety data for IVIG is very positive, making it a promising option for those considering clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about IVIG (Intravenous Immunoglobulin) for Post-COVID Syndrome because it offers a unique approach compared to standard treatments, which typically focus on symptom management like pain relief and physiotherapy. Unlike these options, IVIG is derived from plasma and works by supplying antibodies that can modulate the immune system, potentially addressing underlying immune dysfunction in Post-COVID Syndrome. This mechanism could help reduce inflammation and improve recovery times, offering hope for those struggling with long-term symptoms.

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

Research has shown that intravenous immunoglobulin (IVIG) can help treat symptoms of Long COVID. One study found that high doses of IVIG improved conditions in people with Long COVID. IVIG has also shown promise in treating various nerve and immune system conditions and symptoms related to Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Additionally, IVIG was linked to improvement in patients with COVID-19 pneumonia and may help clear the virus in people with weakened immune systems. In this trial, participants will receive either IVIG or a placebo, with some receiving coordinated care and others receiving usual care. These findings suggest that IVIG could be a helpful treatment for managing post-COVID syndrome symptoms. ^{1 6 7 8 9}

Who Is on the Research Team?

Christopher Grainger, MD

Principal Investigator

Duke Clinical Research Institute

Peter Novak, MD

Principal Investigator

Harvard

Pam Taub, MD

Principal Investigator

University of California, San Diego

Tae Chung, MD

Principal Investigator

Johns Hopkins University

Cyndya Shibao, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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 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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9932260/

Long-term high-dose immunoglobulin successfully treats Long ... Long-term high-dose immunoglobulin therapy is an effective therapeutic option for treating patients with Long COVID.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0889159124006482

A review of intravenous immunoglobulin in the treatment ... This review provides a comprehensive update on the use of IVIG in multiple neuroimmune conditions, ME/CFS, acute COVID-19, and PASC

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04500067

Intravenous Immunoglobulin (IVIG, Bioven) Efficacy Assess ... The patient's condition is assessed daily till discharge; and by schedule after discharge (if it happen earlier), during 28 days period after diagnosis of ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7151471/

Effect of regular intravenous immunoglobulin therapy on ... The data in this study allowed for a preliminary evaluation of the efficacy of IVIG therapy in critically ill patients with COVID-19 pneumonia.

5. sciencedirect.com sciencedirect.com/science/article/pii/S1201971224001176

Intravenous immunoglobulin therapy for COVID-19 in ... Treatment with IVIG was associated with clinical cure and viral clearance in immunocompromised patients. Our data suggests that IVIG could be a novel treatment ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10166837/

Efficacy of intravenous immunoglobulin (IVIg) on COVID-19 ... IVIg therapy has been used in several COVID-19-related neurological diseases, including polyneuropathies, encephalitis, and status epilepticus, and results ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04661839

NCT04661839 | A COVID-19 Study to Evaluate Safety and ... This study is designed to evaluate three dose levels of Anti-SARS-CoV-2 Immunoglobulin Intravenous (Human) (COVID-HIGIV) for safety and pharmacokinetics ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT05350774

Immunotherapy for Neurological Post-Acute Sequelae of ... This study will evaluate the clinical and laboratory effects of immunoglobulin therapy in patients who recovered from acute mild-moderate COVID-19 infection but ...

9. ijidonline.com ijidonline.com/article/S1201-9712(24)00117-6/fulltext

Intravenous immunoglobulin therapy for COVID-19 in ... Treatment with IVIG was associated with clinical cure and viral clearance in immunocompromised patients. Our data suggests that IVIG could be a novel treatment ...