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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05350774
Recruitment Status : Enrolling by invitation
First Posted : April 28, 2022
Last Update Posted : December 5, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

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:

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

    1. Montreal Cognitive Assessment (MoCA)
    2. Brief tablet-based Neuropsychiatric evaluation
    3. Karnofsky Performance Status (KPS)
    4. 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:

    1. Cytokine levels
    2. Cell markers per flow cytometry

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Study Type : Interventional  (Clinical Trial)
Estimated 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)
Estimated Study Start Date : December 8, 2022
Estimated Primary Completion Date : December 30, 2022
Estimated Study Completion Date : December 30, 2022

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Effects of immunotherapies in patients [ Time Frame: 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 :
  1. Investigate laboratory effects [ Time Frame: 4 weeks after treatment ]
    To investigate laboratory effects of immunotherapies in patients with neurological post-acute sequelae of SARS-CoV-2 infection.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05350774


Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: Avindra Nath, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
Additional Information:
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Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier: NCT05350774    
Other Study ID Numbers: 10000711
000711-N
First Posted: April 28, 2022    Key Record Dates
Last Update Posted: December 5, 2022
Last Verified: June 16, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):
COVID-19
Long Haul Covid
Additional relevant MeSH terms:
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Thrombosis
Inflammation
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Methylprednisolone
Immunoglobulins
Immunoglobulins, Intravenous
gamma-Globulins
Rho(D) Immune Globulin
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Immunologic Factors