Immunotherapy for Long-Haul COVID

Overseen By Amanda M Wiebold

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Must not be taking: Oral steroids, Immunosuppressives

Disqualifiers: Traumatic brain injury, Substance use, others

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

Compensation: Varies

Number of Visits: 11

Duration: 2 weeks

45 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: COVID-19 can cause problems in different parts of the body. For most people, it causes fevers or trouble breathing. Some people might not recover all the way. Researchers want to see if a treatment can help with people who have recovered from COVID-19 but still have symptoms ("Long COVID"). Objective: To learn if human immunoglobulin (IVIG) will help with neurological symptoms of Long COVID. Eligibility: Adults ages 18 and older who had COVID-19 at least 12 weeks ago and have ongoing neurologic symptoms, such as dizziness, trouble walking, or problems with strength. Design: Participants will be screened with a medical record review. Participants will have a medical history and a physical exam and complete questionnaires about their health and quality of life. They will have a spinal tap. They will give blood samples. They will discuss their symptoms with a neurologist and have a neurological exam. Participants will take memory and thinking tests using a tablet. The tests will take 1 hour to complete. They will also take a smell and taste test. It will take approximately 30 minutes to complete. Participants will lie on a table that tilts for up to 40 minutes. Their blood pressure and heart rate will be monitored. Blood will be taken through an intravenous (IV) catheter. Participants will receive either IVIG, or saline by IV for 5 days. Then the participants will receive IVIG if they first received saline or saline if they first received IVIG by IV for another 5 days. They will not know what they receive. Participants will have an MRI of the brain if they have not had one recently. They will receive a contrast agent by IV as part of the MRI scan. Participants will be on the study for up to 4 months. They will have follow-up visits at the clinical center as well as fill out questionnaires at home. They may be asked to continue follow-up....

Will I have to stop taking my current medications?

The trial excludes participants who are currently taking oral steroids or other immunosuppressive medications, so you may need to stop these medications to participate.

What data supports the effectiveness of the treatment IV immunoglobulin for Long-Haul COVID?

Research suggests that high-dose intravenous immunoglobulin (IVIG) can reduce inflammation and improve respiratory function in COVID-19 patients by modulating the immune response, which may be beneficial for Long-Haul COVID patients experiencing similar symptoms. ^{1 2 3 4 5}

Is intravenous immunoglobulin (IVIG) generally safe for humans?

Intravenous immunoglobulin (IVIG) is generally considered safe for humans, with mild side effects being more common and severe complications being rare. Safety studies in animals also showed no signs of toxicity or allergic reactions. ^{6 7 8 9 10}

How does the treatment IV immunoglobulin differ from other treatments for long-haul COVID?

IV immunoglobulin (IVIg) is unique because it provides passive immunity by delivering antibodies from healthy donors, which may include neutralizing antibodies against the COVID-19 virus. This approach is different from other treatments that typically target the virus directly or aim to reduce symptoms, as it enhances the body's immune response by supplementing it with ready-made antibodies. ^{2 11 12 13 14}

Research Team

Avindra Nath, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Eligibility Criteria

Adults over 18 who had mild to moderate COVID-19 at least 12 weeks ago and are now experiencing persistent neurological symptoms like dizziness, cognitive issues, or walking difficulties. They must be willing to follow the study procedures for up to 4 months and have a brain MRI if they haven't already. People with severe psychiatric conditions, recent vaccines, certain medical treatments or conditions that could affect results are excluded.

Inclusion Criteria

Enrolled in the screening phase of Protocol 000089 Post-Coronavirus Disease 19 Convalescence at the National Institutes of Health

I have had or am willing to have a brain MRI after being diagnosed with COVID-19.

I had COVID-19 but it was not severe enough to need hospital or ICU care.

Exclusion Criteria

You cannot have a brain MRI with a contrast agent if you have metal in your body, kidney function below a certain level, are pregnant or breastfeeding, or have severe claustrophobia.

You have certain medical conditions like kidney problems, heart disease, blood clotting disorders, severe allergies, or psychiatric conditions that make it unsafe for you to receive intravenous immunoglobulins.

I cannot have a spinal tap due to certain health issues or medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either IVIG or saline by IV for 5 days, followed by a crossover to the other treatment for another 5 days

2 weeks

Daily visits for 10 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including follow-up visits and questionnaires

up to 4 months

Follow-up visits at the clinical center and questionnaires at home

Treatment Details

Interventions

• IV immunoglobulin

Trial Overview The trial is testing whether IV immunoglobulin (IVIG), compared to saline solution (a placebo), can improve long-term neurological symptoms after COVID-19 recovery. Participants will receive both treatments in different periods without knowing which one they're getting first.

Participant Groups

Group I: IVIg arm Experimental Treatment 1 Intervention

IVIg arm IV immunoglobulin 0.4g/kg/day for 5 days

Group II: Placebo arm Placebo Group 1 Intervention

equivalent volume of Normal Saline for 5 days

Who Is Running the Clinical Trial?

National Institute of Neurological Disorders and Stroke (NINDS)

Lead Sponsor

Trials

1,403

Recruited

655,000+

Findings from Research

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 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]

The development of intravenous anti-COVID-19 hyperimmune immunoglobulin resulted in a product with a high concentration of neutralizing antibodies (9.4 times concentrated) and a protein content of 98.1 mg/ml, primarily consisting of IgG (97.6%).

Safety studies in animal models showed no toxicity or allergic reactions, and the immunoglobulin effectively protected immunosuppressed hamsters from SARS-CoV-2, paving the way for future clinical trials in healthy adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and characterization of anti-SARS-CoV-2 intravenous immunoglobulin from COVID-19 convalescent plasma. Razumikhin, M., Smolyanova, T., Nikolaeva, A., et al.[2022]

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 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]

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]

References

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

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

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

Benefits of high-dose intravenous immunoglobulin on mortality in patients with severe COVID-19: An updated systematic review and meta-analysis. [2023]

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

High-dose intravenous immunoglobulins might modulate inflammation in COVID-19 patients. [2021]

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

Intravenous Immunoglobulin Therapy for Critically Ill COVID-19 Patients With Different Inflammatory Phenotypes: A Multicenter, Retrospective Study. [2022]

5. England pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

Development and characterization of anti-SARS-CoV-2 intravenous immunoglobulin from COVID-19 convalescent plasma. [2022]

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

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

8. Germany pubmed.ncbi.nlm.nih.gov

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

9. England pubmed.ncbi.nlm.nih.gov

Hyperimmune anti-COVID-19 IVIG (C-IVIG) Therapy for Passive Immunization of Severe and Critically Ill COVID-19 Patients: A structured summary of a study protocol for a randomised controlled trial. [2022]

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

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

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

Monoclonal Antibodies and Antivirals against SARS-CoV-2 Reduce the Risk of Long COVID: A Retrospective Propensity Score-Matched Case-Control Study. [2023]

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

Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein. [2023]

13. Japan pubmed.ncbi.nlm.nih.gov

Casirivimab/Imdevimab for Active COVID-19 Pneumonia Which Persisted for Nine Months in a Patient with Follicular Lymphoma during Anti-CD20 Therapy. [2023]

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

Remission of severe forms of long COVID following monoclonal antibody (MCA) infusions: A report of signal index cases and call for targeted research. [2023]