Baseline characteristics

From February 2023 to November 2023, a total of 130 patients underwent screening at eight clinical research centers in China. Among them, 108 patients were randomized to the meplazumab group or placebo group in a 1:1 ratio. A total of 103 patients were included in the intention-to-treat population, and 105 were included in the safety analysis population. In the meplazumab group, 53 subjects received the first dose, among whom 27 subjects received the second dose. In the placebo group, 52 subjects received the first dose, among whom 29 subjects received the second dose. The ratio of received two doses in two groups was balanced (P = 0.56). The 28-day follow-up evaluation was completed in 105 patients (Fig. 1).

Enrollment and trial design. Flowchart depicting the enrollment, allocation, and exclusion process of study participants. AE adverse event, SAE serious adverse event

The median age of the meplazumab group and placebo group was 68.2 and 69.7 years old, respectively. Thirty-two patients (31.1%) were female. All patients had severe COVID-19. A total of 45 patients (43.7%) had received COVID-19 vaccination prior to enrollment. The baseline demographic and clinical characteristics were balanced between the two groups except for “smoking” (Table 1). The comorbidities and medical history were also balanced between the two groups except for “coronary atherosclerosis” and “renal failure” (supplementary Table 1). All patients received standard of care according to the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Tentative 10th Edition), and the concomitant medications, including the details of concomitant use of antiviral agents, glucocorticoids, anticoagulants, and oxygen therapy are listed in the Supplementary Tables 2–4.

Clinical efficacy

On day 28, 1 patient (1.96%, 95% CI: 0.05, 10.45) in the meplazumab group, and 4 (7.69%, 95% CI: 2.14, 18.54) in the placebo group had died. A decreased all-cause mortality was observed in the meplazumab group compared to the placebo group, with the difference not being statistically significant (P = 0.170) and the rate difference at 5.72% (95% CI: −2.46, 13.90).

The supplementary analysis using composite strategy showed that on day 28, the all-cause mortality was 3.92% (95% CI: 0.48, 13.46) in the meplazumab group and 15.38% (95% CI: 6.88, 28.08) in the placebo group (P = 0.044), and the rate difference between the two groups was 11.44% (95% CI: 0.30, 22.58) with a relatively lower rate of 74.5% in the meplazumab (Table 2). Furthermore, subgroup analyses of the primary efficacy endpoints based on smoking showed that the all-cause mortality on day 28 was 4.76% (95% CI: 0.12, 23.82) in the meplazumab group and 33.33% (95% CI: 9.92, 65.11) in the placebo group (P = 0.047, Supplementary Table 5) with the rate difference of 28.57% (95% CI: 2.88, 57.59).

The short-term efficacy of the meplazumab was evaluated on day 14, where the all-cause mortality was 0% (95% CI: 0.00, 6.98) in the meplazumab group and 3.85% (95% CI: 0.47, 13.21) in the placebo group (P = 0.150) with rate difference 3.83% (95% CI: −1.39%, 9.05%). The supplementary analysis showed that all-cause mortality on day 14 was 1.96% (95% CI: 0.05, 10.45) in the meplazumab group and 13.46% (95% CI: 5.59, 25.79) in the placebo group, with a rate difference of 11.49% (95% CI: 1.46, 21.52), and the relatively decreased rate was 85.4% in the meplazumab group (P = 0.025, Table 2).

The long-term therapeutic effect was assessed using the all-cause mortality on day 56, which was 1.96% (95% CI: 0.05, 10.45) in the meplazumab group and 11.54% (95% CI: 4.35, 23.44) in the placebo group, with a rate difference of 9.58% (95% CI: 0.08, 19.07), and the relatively decreased rate was 83.0% in the meplazumab group (P = 0.048, Table 2). The supplementary analysis showed that all-cause mortality in the meplazumab group and placebo group was 3.92% (95% CI: 0.48, 13.46) and 15.38% (95% CI: 6.88, 28.08), respectively, with a rate difference of 11.44% (95% CI: 0.30, 22.58), and the relatively decreased rate was 74.5% in the meplazumab group (P = 0.044, Table 2).

The assessment of other secondary endpoints also indicated potential benefits for patients treated with meplazumab, including a 5.58% increase in the discharge rate on day 28 in the meplazumab group compared to the placebo group (90.20% vs 84.62%). Additionally, the rate of sustained clinical improvement by day 28 was increased by 7.47% in the meplazumab group compared to the placebo group (88.24% vs 80.77%).

The meplazumab group had 27 subjects (52.94%) admitted to the ICU, with a median ICU stay of 11 days, whereas the placebo group had 31 cases (59.62%) admitted to the ICU, with a median ICU stay of 12 days. This indicates that the meplazumab group had a 6.68% lower rate of ICU admission than the placebo group.

Viral load is associated with the body’s immune response, disease severity, and mortality in COVID-19.^27,28 In this study, the nucleic acid-negative conversion rate and the nucleic acid-negative conversion time were analyzed using the Kaplan–Meier method. As shown in supplementary Table 6, from day 7 to day 56, the nucleic acid-negative conversion rates at various time points were consistently higher in the meplazumab group than in the placebo group. Particularly, the nucleic acid-negative conversion rate on day 7 was improved by 11.69% in the meplazumab group compared to the placebo group (57.14% vs 45.45%). The median time to nucleic acid-negative conversion in the meplazumab group was 7 days, compared to 9 days in the placebo group. The viral genomic copy number was evaluated using the cycle threshold values of the ORF1ab gene of SARS-CoV-2. As shown in Supplementary Table 7, the cycle threshold changes from baseline were higher in the meplazumab group than in the placebo group, indicating the viral load was reduced by meplazumab.

Safety

In this study, 0.2 mg/kg meplazumab demonstrated good safety and tolerability in patients with severe COVID-19. Most adverse events were consistent with the reported complications in COVID-19, and the majority of adverse events were considered not associated with meplazumab by the investigators. Drug-related adverse events were observed in 6 patients (11.32%) in the meplazumab group and 5 patients (9.62%) in the placebo group. The meplazumab group had 1 patient reporting an adverse event (fever) leading to drug discontinuation (Table 3 and Supplementary Tables 8 and 9). No grade ≥ 3 adverse reactions were observed.