Effect of degalactosylated bovine glycoprotein formulations MAF and M сapsules on lymphopenia and clinical outcomes in hospitalized COVID-19 patients: a randomized clinical trial

Abstract

Background: Targeting mucosal immunity of the gut, which is known to provide antigen processing, while avoiding excessive or unnecessary inflammation, was tested as a way to modulate COVID-19 severity.

Methods: Randomized open-label trial in 204 adults hospitalized with non-critical COVID-19 who received for 14 days in addition to standard of care (SOC) degalactosylated bovine glycoproteins formulations of either MAF capsules (MAF group) or M capsules (M group) or SOC only (control group).

Results: Median recovery time when patients did not require supplemental oxygen was 6 days in both study groups compared to 9 days in the control (MAF vs. control; P = 0.020 and M vs. control; P = 0.004). A greater reduction in mortality was seen in the MAF group compared to the control by day 14 (8.3% vs. 1.6%; P = 0.121) and by day 29 (15.3% vs. 3.2%; P = 0.020), and similarly in the M group by day 14 (8.3% vs. 2.9%; P = 0.276) and by day 29 (15.3% vs. 2.9%; P = 0.017). The proportion of those who had baseline absolute lymphocyte count (ALC) lower than 0.8 × 10⁹/L was 13/63 (20.6%), 17/69 (24.6%), and 18/72 (25.0%) of patients in MAF, M, and control group respectively. Day 29 mortality among these lymphopenic patients was three times higher than for the intent-to-treat population (21% vs. 7%) and consisted in above subgroups: 2/13 (15%), 2/17 (12%), and 6/18 (33%) of patients. The decreased mortality in both study subgroups correlated with greater ALC restoration above 0.8 × 10⁹/L level seen on day 14 in 91% (11/12) and 87.5% (14/16) of survivors in MAF and M subgroups respectively compared to 53.3% (8/15) of survivors in control subgroup. Incidences of any ALC decrease below the baseline level on day 14 occurred in 25.4% of patients in the MAF group and 29.0% of patients in the M group compared to 45.8% in control and ALC depletion by ≥ 50% from the baseline level consisted of 7.9%, 5.8%, and 15.3% of cases in these groups respectively.

Conclusion: This study showed that both study agents prevented ALC depletion and accelerated its restoration, which is believed to be one of the mechanisms of improved crucial clinical outcomes in hospitalized COVID-19 patients.

Trial registration: The trial was registered after the trial start in ClinicalTrials.gov NCT04762628, registered 21/02/2021, https://www.

Clinicaltrials: gov/ct2/show/NCT04762628 .

Keywords: COVID-19 treatment; Lymphopenia; Mortality; Mucosal immunity; Saisei M capsules; Saisei MAF capsules.

Fig. 1

Kaplan-Meier curve comparing survival of groups MAF, M, and control Focusing on 29-day mortality as one of the primary outcomes, each line on the Kaplan-Meier curve depicts the estimated probability of surviving over 29 days from study treatment started for each group. The log rank test used to compare the survival times between three study groups

Fig. 2

Changes in mean ALC values in 10⁹ cells/L over a two-week treatment period in subgroups of participants with lymphopenia at enrolment

Fig. 3

Distribution of patients in subgroups with ALC at enrolment below 1.0 × 10⁹/L (left) and in subgroups with ALC at enrolment below 0.8 × 10⁹/L (right) based on ALC recovery above these thresholds and mortality cases on Day 7 and Day 14* Abbreviations ALC, Absolute Lymphocyte Count; Control, Control subgroup; MAF, MAF subgroup; M, M subgroup.* Figure 2 visualizes the data presented in Table 8. This figure displays the distribution of the absolute number of patients in the lymphopenic subgroups of the study groups based on their ALC recovery above the indicated thresholds on Day 1 and Day 7 (whether achieved or not) and displays mortality cases