Immunotherapy for Neurological Post-Acute Sequelae of SARS-CoV-2

Study Description:

This study will evaluate the clinical and laboratory effects of immunoglobulin therapy in patients who recovered from acute mild-moderate COVID-19 infection but still have persistent neurologic symptoms. Despite clinical recovery from the acute infection, some individuals continue to experience ongoing symptoms, at times several months after recovery, and many of these symptoms are neurologic. Some features suggest that this is a post-infectious immune-mediated process, and anecdotally patients have responded well to immunoglobulin therapy. This study will evaluate the clinical and laboratory effects of intravenous immunoglobulin therapy compared to placebo using a cross-over trial design. It is hypothesized that immunoglobulin therapy could have positive clinical and laboratory effects on patients with persistent neurological symptoms.

Objectives:

Primary Objective: To compare the clinical efficacy of intravenous immunoglobulin therapy to placebo in ameliorating the neurological post-acute sequalae of SARS-CoV-2 infection.

Secondary objective: To determine the clinical effects of intravenous immunoglobulin therapy in patients with neurological post-acute sequalae of SARS-CoV-2 infection.

Exploratory objective: To investigate the laboratory effects of intravenous immunoglobulin therapy in patients with neurological post-acute sequalae of SARS-CoV-2 infection.

Endpoints:

Primary endpoint:

Proportion of participants with a clinically meaningful change in Health Utilities Index Mark 3 (HUI3) 2 weeks after intravenous immunoglobulin therapy compared with 2 weeks after placebo.

Secondary endpoints:

• Change in functional / patient-reported scales:

• WHO post COVID-19 functional scale
• Post-COVID-19 Functional Status (PCFS) scale (0-4).
• COVID-19 Yorkshire Rehabilitation Scale
• PROMIS Global Health score
• PROMIS Depression score
• PROMIS anxiety score
• Change in clinical scales:

• Montreal Cognitive Assessment (MoCA)
• Brief tablet-based Neuropsychiatric evaluation
• Karnofsky Performance Status (KPS)

Exploratory endpoints:

• Autonomic testing - Change in the number and character of test results indicating autonomic nervous system dysfunctions as evidenced by abnormal physiological responses to the Valsalva maneuver or head-up tilting.
• Change in immunological markers:

• Cytokine levels
• Cell markers per flow cytometry
• SCENTinel, Olfactory testing, Monell

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Male or female, aged at least 18 and older.
• Meets the inclusion/exclusion criteria and is enrolled in Phase A of Protocol 000089 "Post-Coronavirus Disease 19 Convalescence at the National Institutes of Health."
• Previously diagnosed with mild-moderate COVID-19 (WHO Clinical Progression Scale between 2-5. Patients with severe acute COVID-19 requiring hospitalization or ICU care are excluded. Enrollment could take place 12 weeks after the diagnosis of acute COVID-19.
• Prior COVID-19 diagnosis confirmed by patient reported infection followed by confirmatory nucleocapsid antibody testing or a positive SARS-CoV-2 PCR test result from the time of infection.
• Exhibiting persistent neurologic symptoms evidenced by a self-reported illness narrative of the development of persistent PASC symptoms after recovering from a SARS-CoV-2 infection. These include symptoms such as fatigue, cognitive difficulties, orthostatic intolerance, and any ongoing issues with gait instability, vision, speech, swallowing, sensation or strength.
• Non-negligible PASC symptom severity, as determined using PCFS (minimal score of 2).
• Ability of subject to understand and the willingness to sign a written informed consent document.
• Prior completion of a clinical brain MRI after the diagnosis of COVID-19, or willingness to complete a brain MRI.
• Meets current Clinical Center HES' policy for discontinuing isolation and quarantine for COVID-19.

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• For participants who have not completed a brain MRI since onset of symptoms: inability to complete brain MRI with gadolinium including contraindicated metal in the body, prior allergic reaction to gadolinium, eGFR <45 mmol/L, pregnancy or lactation, or claustrophobia that is unable to be adequately treated with a low dose oral

benzodiazepine.

• Contraindication to a research lumbar puncture, including use of anticoagulant medication, platelets < 50,000/uL, PT or PTT >1.5 x ULN for the NIH Clinical Center, or otherwise inability to complete the procedure.
• A condition that would significantly confound interpretation of the clinical and research tests as determined by the study investigators. This could include: traumatic brain injury, substance use disorder, active malignancy, systemic immunologic disorders, current or previous long-term immune suppressive therapy.
• Received a SARS-CoV-2 vaccine dose within less than 4 weeks of enrollment or is planning for any additional vaccines during the course of the study.
• Prior experimental treatment for PASC with immunoglobulins.
• Current medications include oral steroids or other immunosuppressive medications.
• Active participation in a clinical protocol which includes any intervention that may affect the results of the current study.
• Contraindication of intravenous immunoglobulins, including:

• Renal insufficiency (eGFR<45mmol/L)
• IgA deficiency
• History of ischemic heart disease
• Peripheral vascular disease
• Cerebrovascular disease
• Previously diagnosed hypercoagulability syndrome including antiphospholipid antibody syndrome, Protein C/S deficiency, Factor V Leiden, Antithrombin deficiency, MTHFR homozygosity
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3.0 times the upper limit of normal.precluding the use of acetaminophen.
• Previously documented anaphylaxis or severe systemic reaction to immunoglobulins, acetaminophen, or diphenhydramine.
• A severe psychiatric condition, which based on the assessment of the study investigators, will impact the ability to complete the 12-week study course.