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

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS) (NIH)

Overall Status

Enrolling by invitation

CT.gov ID

NCT05350774

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 2 treatments can help with people who have recovered from COVID-19 but still have symptoms ( Long-Haul COVID ).

Objective:

To learn if methylprednisolone (steroid) and human immunoglobulin (IVIG) will help with symptoms of Long-Haul COVID.

Eligibility:

Adults ages 18 and older who had COVID-19 at least 6 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 physical exam and chest x-ray. They will 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 an exam.

Participants will take memory and thinking tests using pen and paper. The tests will take 10-15 minutes to complete. They will also take a smell test with scratch-and-sniff books. It will take 5-10 minutes to complete.

Participants will lie on a table that tilts. Their blood pressure and heart rate will be monitored. Blood will be taken through an intravenous (IV) catheter.

Participants will receive either the steroid, IVIG, or saline by IV for 5 days. They will not know which treatment they get.

Participants may have an optional MRI of the brain and spine. They will receive a contrast agent by IV.

Participants will be on the study for up to 3 months. They may be asked to continue follow-up.

Condition or Disease	Intervention/Treatment	Phase
Systemic Inflammation Neuroinflammation Microvascular Thrombosis	Drug: IV immunoglobulin Drug: IV normal saline Drug: IV methylprednisolone	Phase 2

Detailed Description

Study Description:

This study will evaluate the clinical and laboratory effects of immunotherapies in patients who recovered from acute mildmoderate 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 immunotherapies. This study will evaluate the clinical and laboratory effects of the different proposed immunological interventions compared to placebo. It is hypothesized that these interventions could have positive clinical and laboratory effects on patients with persistent neurological symptoms.

Objectives:

Primary Objective: To compare the clinical effects of three study arms (intravenous immunoglobulin, intravenous steroids, or placebo) in participants with neurological post-acute sequalae of SARS-CoV-2 infection.

Secondary objective: To investigate laboratory effects of immunotherapies 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) 4 weeks after study intervention

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)
University of Pennsylvania Smell Identification Test (UPSIT)

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

Cytokine levels
Cell markers per flow cytometry

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Immunotherapy for Neurological Post-Acute Sequelae of SARS-CoV-2 (IN-PASC)

Anticipated Study Start Date :

Aug 30, 2022

Anticipated Primary Completion Date :

Dec 30, 2022

Anticipated Study Completion Date :

Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IVIg arm IVIg arm IV immunoglobulin 0.4g/kg/day for 5 days	Drug: IV immunoglobulin IVIg IV immunoglobulin 0.4g/kg/day for 5 days
Placebo Comparator: Placebo arm IV normal saline 250ml for 5 days	Drug: IV normal saline IV normal saline 250ml for 5 days
Experimental: Steroid arm Steroid arm IV methylprednisolone 1g/day for 5 days	Drug: IV methylprednisolone Steroid - IV methylprednisolone 1g/day for 5 days

Arm

Intervention/Treatment

Experimental: IVIg arm

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

Drug: IV immunoglobulin

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

Placebo Comparator: Placebo arm

IV normal saline 250ml for 5 days

Drug: IV normal saline

IV normal saline 250ml for 5 days

Experimental: Steroid arm

Steroid arm IV methylprednisolone 1g/day for 5 days

Drug: IV methylprednisolone

Steroid - IV methylprednisolone 1g/day for 5 days

Outcome Measures

Primary Outcome Measures

Effects of immunotherapies in patients [4 weeks after treatment]
The primary outcome measure is the proportion of participants with a clinically meaningful improvement in Health Utilities Index Mark 3 (HUI3) 4 weeks after study intervention.

Secondary Outcome Measures

Investigate laboratory effects [4 weeks after treatment]
To investigate laboratory effects of immunotherapies in patients with neurological post-acute sequelae of SARS-CoV-2 infection.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.
Enrolled in the screening phase 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). Enrollment could take place between 12 weeks and 18 months after the diagnosis of acute COVID-19.
Prior COVID-19 diagnosis confirmed by patient reported positive antigen test for SARSCoV-2 with confirmatory nucleocapsid antibody testing at screening or a positive SARSCoV-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.
Contraindication to autonomic testing, including refractory ventricular arrhythmias or symptomatic coronary artery disease.
A condition prior to the diagnosis of COVID-19 infection 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 IV steroids or 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.
Diabetes mellitus treated with medications or HbA1c >6.5.
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 steroids, immunoglobulins, acetaminophen, or diphenhydramine.
Active or latent TB as evidenced by history of respiratory symptoms or of untreated or partially treated tuberculosis or a chest radiograph showing active infection or residual changes indicative of untreated prior TB infection on a chest radiograph (e.g. calcified granulomas, Gohn focus or complex, apical scarring).
A severe psychiatric condition prior to the diagnosis of COVID-19, which based on the assessment of the study investigators, will significantly increase the risk of psychiatric side effects from IV steroids.