A Randomized Controlled Study Assessing Convalescent Immunoglobulins vs Convalescent Plasma for Hospitalized Patients With Coronavirus 2019

The study addresses whether convalescent immunoglobulins (cIgG), a purified, concentrated, and diversified antibody product derived from multiple convalescent plasma donors, provide clinical benefit compared with high-titer convalescent plasma (CP) in high-risk hospitalized COVID-19 patients. Prior literature on CP has shown conflicting results, with benefit linked to higher antibody titers and earlier administration. Monoclonal antibodies offered convenience but lost efficacy with emerging variants and are costly. cIgG may offer higher antibody dose, broader epitope diversity, and easier administration without blood typing, potentially retaining effectiveness against variants. The study’s primary objective was to evaluate noninferiority of cIgG vs two high-titer CP units by day 14 clinical improvement on the WHO 8-point scale, and to assess safety.

Publications on CP have yielded mixed findings: some reported improved outcomes and reduced mortality, especially with early administration and higher antibody titers, while others failed to show benefit. Efficacy correlates with antibody levels and timing (better early in illness). As the pandemic evolved, monoclonal antibodies became prominent due to ease of use but faced issues with immune escape by new variants and high costs, limiting use, particularly in low-income settings. cIgG, purified from pooled CP, can offer higher antibody concentration and greater diversity, potentially mitigating variant escape while avoiding blood typing. Prior evidence on cIgG is limited and mixed; a Cochrane review could not conclude benefit, though a small randomized study suggested reduced mortality without statistical significance, likely due to small sample size.

Design: Randomized, controlled, open-label, phase II, multicenter noninferiority trial in Israel, coordinated by Wolfson Medical Center. Enrollment from 14 January 2021 to 12 November 2021 at six centers. Randomization 1:1 to cIgG or high-titer CP, in addition to standard of care. Ethics approvals obtained; written informed consent required. An initial compassionate use phase (n=61) transitioned to the formal trial with identical procedures. Participants: Hospitalized adults ≥18 years with RT-PCR–confirmed SARS-CoV-2; evidence of lung infiltrates; ≤4 days from hospitalization and ≤10 days from symptom onset; oxygen saturation on room air <95% or, if ≥95%, required risk factors (age ≥70; or age 50–69 with ≥2 risk factors; or age <50 with ≥4 risk factors). Risk factors included BMI ≥30, diabetes, cardiovascular disease, chronic lung disease (including ≥10 years cumulative smoking), chronic renal insufficiency, chronic liver disease, neurological disease, active malignancy, immunosuppression, and organ transplantation. Key exclusions: mechanical ventilation, neutropenia <500/μL, true bacteremia, failure of ≥3 organ systems, cirrhosis Child-Pugh C, NYHA ≥II heart failure, chronic lung disease requiring continuous oxygen, IgA deficiency, known sensitivity to blood products, life expectancy <6 months, or DNR order. Interventions: cIgG arm received 4 g cIgG IV once. CP arm received two 200 mL units of high-titer CP from different donors on two consecutive days. Standard treatments were permitted in both arms. Study products: cIgG manufactured by Kamada from CP collected Sept–Dec 2020 using FDA-approved IgG purification with multiple chromatography and viral inactivation steps; final concentration 50 mg/mL. Binding antibody concentration: geometric mean 3051 BAU/mL (≈433 AU/mL), with geometric mean neutralizing titer 553 IU/mL; neutralization 10-fold higher than the pooled CP starting material. CP qualification used Abbott IgG assays: anti-N S/CO thresholds (≥7.0 and ≥4.0 for the two units; average ≥4.5) early in the trial, and anti-S quantitative assay later (anti-S ≥1050 AU/mL deemed high). Based on WHO standard, BAU/mL = 0.142 × AU/mL. Two CP units contained approximately 25%–50% of the antibodies administered by the cIgG dose. Outcomes: Primary endpoint: proportion with improvement of ≥2 points on the WHO 8-point ordinal scale by day 14 from baseline. Secondary endpoints: improvement of ≥1 and ≥2 points on days 7 and 28; survival on days 14 and 28; proportion requiring mechanical ventilation; time to discharge. Subgroup analyses by vaccination status (≥1 vaccine dose vs unvaccinated) and by time from symptom onset to treatment (≤7 vs >7 days). Safety endpoints: treatment-emergent adverse events of special interest (anaphylaxis, serious allergic responses) and serious adverse events. Assessments: WHO ordinal scale recorded at baseline (first dose) and days 7, 14, and 28. Survival assessed to day 28. Statistical analysis: Sample size assumed 75% improvement with CP and 80% with cIgG by day 14, requiring n=270 for noninferiority (margin 10%) with 80% power using the Farrington-Manning method (one-sided α=0.025). If noninferiority established, superiority was to be tested via Fisher exact test (two-sided α=0.05) when the CI lower bound exceeded 10%. A 95% Clopper-Pearson CI was used for secondary endpoints. Analyses conducted in SAS 9.4+. Trial registration: My Trials MOH_2021-01-14_009667.

- Participants: 319 randomized and treated (cIgG n=166; CP n=153). Baseline characteristics were similar (median age 64–66 years; similar comorbidities and baseline WHO scores). Median time from symptom onset to treatment: 7 vs 6 days. - Primary endpoint (day 14 ≥2-point WHO improvement): 67.5% cIgG (112/166) vs 67.3% CP (103/153); difference 0.1% (95% CI −10.1 to 10.4); noninferiority P = .026, failing the 10% noninferiority margin. - Secondary endpoints: • Day 28 ≥2-point improvement: 81.9% cIgG (136/166) vs 70.6% CP (108/153); difference 11.3% (95% CI 1.9–20.7); superiority P = .018. • Day 28 ≥1-point improvement: 84.3% vs 75.8%; difference 8.5% (95% CI −0.4 to 17.4). • Mechanical ventilation: 10.2% cIgG (17/166) vs 16.3% CP (25/153); P = .136. • Mortality by day 14/28 (reported as within 14 days): 9.6% cIgG (16/166) vs 15% CP (23/153); P = .172. Kaplan-Meier analysis showed no treatment-related deaths. • Time to discharge: median 7 days in both groups (P = .309). - Subgroups: • Treatment timing (≤7 vs >7 days from symptom onset): no significant effect on response differences between groups. • Unvaccinated: day 28 improvement 84.1% cIgG vs 66.1% CP (P = .024); survival 89.9% cIgG vs 77.4% CP (P = .066). Day 14 trends favored cIgG but did not reach superiority. • Vaccinated (≥1 dose): differences less pronounced; cIgG did not show survival benefit over CP. - Safety: Two mild urticaria events in the CP group; no anaphylaxis. Serious adverse events attributed to COVID-19 rather than study treatments.

cIgG did not meet the predefined noninferiority criterion versus high-titer CP at day 14, but demonstrated superior clinical improvement by day 28, with trends toward reduced mechanical ventilation and mortality. The benefit was particularly notable in unvaccinated patients, where cIgG achieved superiority in clinical improvement and showed a survival advantage trend. These findings align with the biologic rationale for cIgG—higher antibody titers and greater epitope diversity from pooled donors potentially enhance neutralization breadth and immunomodulatory effects compared with two CP units. Although prior systematic reviews on hyperimmune immunoglobulin reported mixed evidence, the present randomized multicenter study supports cIgG’s efficacy over CP by day 28 in hospitalized high-risk patients, especially among the unvaccinated. The safety profile of both interventions was acceptable, with minimal infusion-related reactions and no treatment-attributed deaths. Antibody dose likely contributed to outcomes: cIgG provided substantially higher antibody levels (approximately 2400 BAU/mL anti-S equivalent) than two CP units, and administering additional CP to match cIgG titers would pose volume and safety challenges in this patient population. Given the diminished activity of many monoclonal antibodies against emerging variants and their costs, cIgG represents a practical alternative that does not require blood typing and can be adapted to variant circulation.

cIgG failed to meet noninferiority versus high-titer CP at day 14 but achieved superior clinical improvement by day 28, with particularly favorable outcomes in unvaccinated patients and an overall acceptable safety profile. These results suggest cIgG is a viable treatment option for hospitalized high-risk COVID-19 patients, especially amid variant evolution and limited monoclonal antibody efficacy. Future research should evaluate earlier administration (e.g., in the outpatient setting soon after symptom onset), optimize dosing strategies, and assess efficacy across variant waves and vaccination strata.

- Timing: Treatment allowed up to 10 days from symptom onset and up to 4 days post-hospitalization; earlier administration may have yielded greater benefit. - Disease stage: Inclusion of patients without risk factors but with oxygen desaturation likely captured more advanced/inflammatory stages where antibodies are less effective; excluding such patients might have clarified efficacy. - Antibody measurement: Transition from anti-N to anti-S assays prevents direct comparison of titers across all CP units; exact antibody titers of administered CP units were not available, although all units were high-titer by predefined criteria. - Dose/volume constraints: To match cIgG antibody dose, substantially more CP would be needed, which is impractical due to volume overload risk in elderly/comorbid patients. - Open-label design could introduce bias, although objective outcomes and standardized scales were used.