A Multicenter, Randomized, Double Blind, Placebo Controlled Phase II Trial of Intravenous Inflammasome Inhibitor (NuSepin) for the Treatment of COVID-19 Patients

Seung-Yong Seong, Catalina Luca, Cosmina Magdau, Olga Adriana Caliman-Sturdza, Andrei Cemurtan, Seunghwa Lee, Sun-Ae Han

Background: More effective and safer anti-inflammatory drugs are necessary to improve clinical outcomes and prevent long term sequelae of patients with COVID-19 pneumoniae.

Objectives: Here we evaluated whether a novel inflammasome inhibitor (NuSepin) provides greater benefit than placebo in patients with COVID-19 pneumonia.

Methods: We conducted a double-blind, randomized, placebo controlled phase ii trial of intravenous NuSepin, which is an NLRP3 inflammasome inhibitor targeting GPCR19, in adults who were hospitalized with COVID-19 pneumoniae in Romania from September 2020 to March 2021. Patients were randomly assigned to receive 0.1 mg/kg NuSepin, 0.2 mg/kg NuSepin, or placebo (b.i.d., i.v. infusion) for up to 14 d or until complete remission, together with standardof care, and were monitored for another 14 d. The primary outcome was theTime to Clinical Improvement (TTCI), defined as a decline of two Ordinal Scales(OS) from randomization on a six category OS that ranges from 1 (dischargedwith normal activity) to 6 (death) (primary TTCI,=TTCI_P). In addition, clinical improvement was also assessed by aggregated National Early Warning Score 2(NEWS2), and secondary TTCI (TTCI_S) was defined by time to NEWS2=0 fromrandomization, which is maintained for 24 h.

Results: By pairwise comparison of TTCI_P, NuSepin 0.2 mg/kg showed a 1.34-fold (95%CI:0.70~2.59) and 1.93-fold (95% CI: 0.96~3.85) higher recoveryRate Ratio (RR) than placebo in modified Intention to Treatment (mITT) set andin Per-Protocol (PP) set, respectively. The median difference in TTCI_S was 3.5days between the NuSepin 0.2 mg/kg group and the placebo group (p=0.016,PP set with baseline NEWS2 ≥ 5), which favored improved recovery in theNuSepin group. The overall RR was 3.4, which favors the NuSepin 0.2 mg/kggroup when the effects of covariates (use of anti-viral drugs and baselineNEWS2 ≥ 5) were adjusted (p=0.0026). At day 4, CRP levels in 52% of patientsin the NuSepin 0.2 mg/kg group returned within the normal range, which iscomparable to 20% of patients in the placebo group. At the end of the studyday, blood pro-inflammatory cytokines levels were significantly lower in theNuSepin group and the percentage of patients with pro-inflammatory cytokineswithin normal ranges were higher in the NuSepin group (35%~60%) than theplacebo group (11%~33%). Serious adverse events were reported in a patient who received NuSepin 0.2 mg/kg (4.5%), but this was found to be unrelated to NuSepin treatment.

Conclusions: Considering the facts that (1) NuSepin has a favorable and tolerable safety profile and (2) a significant increase in RR and a reduction in the time to NEW2=0 was observed, and (3) a significant decrease in blood pro-inflammatory cytokines, clinical improvement of hospitalized moderate-to-severe COVID-19 patients might be achieved with NuSepin 0.2 mg/kg significantly faster than placebo.

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