Intravenous Immunoglobulin Replacement Therapy for Persistent COVID-19 in Patients With B-cell Impairment

Intravenous Immunoglobulin Replacement Therapy for Persistent COVID-19 in Patients With B-cell Impairment: a Multicenter Randomized Controlled Trial

This is a multicenter, randomized controlled trial aiming to investigate the efficacy of intravenous immunoglobulin (IVIG) replacement therapy under the hypothesis that immunoglobulin replacement would have therapeutic effects on persistent COVID-19 in patients with B-cell impairment.

Study Overview

• Status: Recruiting
• Conditions: COVID-19
• Intervention / Treatment: Drug: Immunoglobulins

Detailed Description

This project aims to provide passive immunization to patients with persistent COVID-19 who experience inflammation owing to continuous replication of SARS-CoV-2, as a consequence of B-cell impairment that hinders normal antibody formation. As opposed to relying on the non-specific immune mechanism of IVIG in other studies, this trial focuses on the antiviral effect and antibody-dependent cytotoxicity induced by SARS-CoV-2-specific antibodies from plasma donors who have formed high antibody titers through vaccination and breakthrough infections. Thus, in contrast to previous studies, the therapy may demonstrate clinical efficacy. In this work, we aim to elucidate the role of IVIG in treating persistent COVID-19 in patients with B-cell depletion who cannot produce antibodies, and to establish grounds for clinical application of the therapy.

Once the participants voluntarily provide written consent to participate in the trial, they will undergo screening tests, and eligible participants will be randomly assigned to the treatment or control (standard of care) group in a 1:1 ratio.

• Study Type: Interventional
• Enrollment (Estimated): 58
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jaehoon Ko, Ph,MD; Phone Number: +82-10-3592-2631; Email: jaehoon.ko@samsung.com

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Recruiting
    • Jaehoon Ko
    • Contact: Jaehoon Ko; Phone Number: +821035922631; Email: jaehoon.ko@samsung.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntary written consent to participate in the trial
2. Age≥ 19 years
3. Diagnosed as COVID-19: the definitive diagnosis of COVID-19 will be made at a healthcare facility based on COVID-19 tests approved in Korea, such as reverse transcription polymerase chain reaction (RT-PCR), Xpert, film array, and rapid antigen test (RAT).
4. The diagnosis of persistent COVID-19 will be made following the criteria below:

1. No improvement or worsening of symptoms/signs of active inflammation, such as fever, pneumonia, and dyspnea requiring oxygen, even after 2 weeks of the initial symptom onset or diagnosis of COVID-19 (persisting symptoms/signs at or after the third week of illness).
2. The day count for the disease course is based on the symptom onset or diagnosis date, whichever is earlier, with Day 1 being the date of symptom onset or diagnosis. The third week refers to the period including and following Day 15. For the purpose of day count calculation, self-test results using RAT are accepted.

3. Both symptoms and signs indicative of active inflammation must be present. This status corresponds to the Modified WHO clinical progression scale of ≥ 4.

   • Symptoms include at least one of the following.

     1. Fever of 37.8°C or higher lasting for >48 h (determined based on self-measurement and statements from the patient or caregiver, with fevers persisting from Day 13 to Day 15 also accepted)
     2. Persistent cough despite taking appropriate expectorants and cough suppressants
     3. Dyspnea upon walking on a flat surface (modified Medical Research Council grade >2) ② At least one of the following signs of active inflammation must be present.
     1. Pulmonary infiltration suggestive of COVID-19 observed in chest radiograph or computed tomography scan findings. Findings may vary, from ground-glass opacities to patchy consolidation, and are determined by the clinician or radiologist.
     2. Decreased oxygen saturation (PaO2/FiO2 ≤300 mmHg, SpO2 ≤92%, or PaO2 ≤63%) 5. Cases of patients with B-cell impairment:

(1) Patients with B-cell lineage hematologic malignancies, such as B-cell lymphoma or multiple myeloma, who are presumed to have impaired B-cell function owing to B-cell targeting chemotherapy (i.e., those receiving rituximab, CAR-T, Bispecific T-cell engager therapies), or second-line or higher treatments, such as autologous stem cell transplantation (AutoPBSCT) (2) Patients suffering from diseases known to result in B-cell depletion, such as Good's syndrome associated with thymoma (3) Cases of patients with a congenital primary immunodeficiency who have reduced antibody formation and have not undergone IVIG replacement in the past 3 months.

Among these, those who received B-cell targeting chemotherapy within the past 3 months are eligible for enrollment based on clinical criteria, but other patients must confirm the reduction of peripheral B cells to <1% via flow cytometry to be eligible for enrollment.

Exclusion Criteria:

1. Difficulty controlling the underlying disease or life expectancy of <3 months even after COVID-19 is successfully treated.
2. T-cell impairment.

(1)T-cell suppressive drugs (e.g., cyclosporine, tacrolimus) cannot be suspended owing to organ transplantation or autoimmune disorder.

(2) Patients with human immunodeficiency virus (HIV) infection with a CD4 T-cell count <500 cells/μL or persistent detection of HIV viral RNA in the blood.

3. IVIG or COVID-19 convalescent plasma therapy within 3 months of screening 4. History of serious reaction or hypersensitivity to blood, blood products, blood-derived products, IVIG, and IgG 5. Immunoglobulin A (IgA) deficiency or IgA antibodies present 6. Uncontrolled hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg) 7. Hemolytic anemia, hemorrhagic anemia 8. Impaired cardiac function [New York Heart Association Functional Class Ⅲ or IV] 9. High risk for thrombosis/embolism clinically owing to a history of cerebrovascular and cardiovascular disorders, thrombosis, or embolism 10. Cases of pregnant or breastfeeding women 11. Current participation in another clinical trial related to COVID-19 drugs 12. Cases of participants that are inappropriate to participate in the trial based on the investigator's discretion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IVIG administration; The patients who will meet the inclusion criteria will be administered IVIG at a dose of 1,000 mg/kg, divided over 2-3 days. After administration, the patient's condition will be thoroughly observed. In case of adverse effects from an increased administration rate, the rate will be reduced immediately or suspended until symptom improvement. Other standards of care can be continued.	Drug: Immunoglobulins; Dosage is Immunoglobulin 1,000mg/kg IV. It administer over 2~3 days.; Other Names: Immunoglobulins in this study uses commercially avilable drug.
No Intervention: Standard Of Care; The same anti-viral, anti-inflammatory, and anti-coagulation treatment criteria are applied to the treatment group. If the primary endpoint will be not reached by day 14 of randomization, IVIG can be given at a dose of 1,000 mg/kg based on clinicians' discretion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of clinical effectiveness	Clinical recovery	14day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of clinical effectiveness	Clinical recovery	30day and 60day

Collaborators and Investigators

• Sponsor: Jaehoon Ko
• Investigators: Principal Investigator: Jaehoon Ko, Ph,MD, Samsung Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2024
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: December 4, 2023
• First Submitted That Met QC Criteria: December 4, 2023
• First Posted (Actual): December 6, 2023

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 13, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; Chronic Disease; Post-Infectious Disorders; COVID-19; Post-Acute COVID-19 Syndrome; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous
• Other Study ID Numbers: 2023-11-078

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No