Background Severe COVID-19 infection is associated with dysregulated immune response which, in a substantial minority of patients, results in cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS). Inhibition of cytokines or cytokine-associated signal transduction is a promising strategy to ameliorate ARDS associated with CRS. We and others have previously shown that serum free LIGHT (TNFSF14) levels are markedly elevated in patients with COVID-19 pneumonia/ARDS10,11, suggesting that LIGHT neutralization may offer therapeutic benefit to COVID-19 ARDS patients. Methods We conducted a randomized, double-blind, placebo-controlled, multi-center, proof-of-concept clinical trial of CERC-002 in adults with mild to moderate ARDS associated with COVID-19 (n=83). Enrolled patients received a single dose of CERC-002 or placebo, in addition to standard of care that included high dose corticosteroids. The primary efficacy endpoint was alive and free of respiratory failure status through Day 28. Secondary outcomes included alive status at Day 28, free of invasive ventilation through Day 28, and serum free LIGHT levels. Results In patients hospitalized with COVID-19 associated pneumonia and mild to moderate (ARDS), CERC-002 increased the rate of alive and free of respiratory failure status through Day 28 as compared to placebo (83.9% vs 64.5%; p=0.044). Efficacy was highest in the prespecified subgroup of patients 60 years old and older (76.5% vs 47.1%; p=0.042), the population most vulnerable to severe complications and death with COVID-19 infection. Through both the initial 28-day and 60-day follow-up periods, reductions of approximately 50% in mortality were observed for CERC-002 compared to placebo (7.7% vs 14.3% at Day 28 and 10.8% vs 22.5% at Day 60). Importantly, this improvement was incremental to standard of care including high dose steroids and remdesivir 88.0% and 57.8%, respectively). In addition, serum LIGHT levels but not IL-6 levels were markedly reduced in patients treated with CERC-002. Conclusions The data presented herein demonstrate that CERC-002 markedly reduces the risk of respiratory failure and death incremental to standard of care including high dose corticosteroids and reduces LIGHT levels in patients with COVID-19 ARDS. (ClinicalTrials.gov number NCT04412057).

Objectives: An abundance of data exists documenting the association of H. pylori eradication with the reduction in duodenal ulcer recurrence. Aim: To evaluate the validity of using H. pylori eradication as a surrogate marker for the reduction in duodenal ulcer recurrence using rigorously controlled studies. Methods: Three controlled clinical trials were conducted in patients with uncomplicated, active duodenal ulcers. Patients were treated with various combinations of omeprazole and amoxycillin. Ulcer healing and H. pylori eradication were assessed. For patients whose duodenal ulcer healed, duodenal ulcer recurrence was determined over a 6‐month period in patients with H. pylori eradication and those remaining positive for H. pylori at least 4 weeks after treatment. To support the data obtained from these clinical trials, a search of the medical literature was conducted to identify additional human clinical trials in which duodenal ulcer recurrence rates were measured and categorized by H. pylori status at least 1 month post‐treatment. Results: In 11 controlled trials, the overall 6–18‐month duodenal ulcer recurrence rate was 54% among patients remaining positive for H. pylori at least 4 weeks after treatment compared to 6% among patients with H. pylori eradication following treatment. This finding was corroborated by the uncontrolled trials, in which the duodenal ulcer recurrence rate was 64% among patients found to be H. pylori‐positive and 6% for patients found to be H. pylori‐negative at least 4 weeks after treatment. A time course of duodenal ulcer recurrence rates using pooled data from both controlled and uncontrolled studies demonstrated that duodenal ulcer recurrence rates for H. pylori‐negative patients persisted for up to 4 years following treatment. Duodenal ulcer recurrence rates for H. pylori‐positive patients increased for the first year, then levelled off. A comparison of the duodenal ulcer recurrence rates for different treatment regimens revealed that eradication regimens based on omeprazole plus antibiotics and bismuth plus antibiotics exhibited similar duodenal ulcer recurrence rates for H. pylori‐positive and ‐negative patients. Conclusion: Regardless of treatment regimens, H. pylori eradication produced a consistent and significant reduction in duodenal ulcer recurrence. Therefore H. pylori eradication, 4 weeks post‐therapy, can be used as a surrogate marker for reduced duodenal ulcer recurrence in investigational clinical trials.

The prevalence of antineutrophil cytoplasmic antibodies was evaluated in patients with ulcerative colitis, primary sclerosing cholangitis, and various other gastrointestinal and hepatobiliary diseases to define the sensitivity and specificity of the test. The presence of antineutrophil cytoplasmic antibodies was detected in alcohol-fixed cytospin preparations of peripheral blood neutrophils with an indirect immunofluorescence technique. A perinuclear staining pattern was considered positive. Thirty-six of 50 patients (72%) with ulcerative colitis and/or primary sclerosing cholangitis had positive results. Twenty-two of 210 patients (10%) in the control group had positive findings, including a significant proportion of patients with autoimmune hepatitis (50%) and non-A, non-B and non-C hepatitis (27%). This test for antineutrophil cytoplasmic antibodies has a sensitivity of 72% and specificity of 90% for either ulcerative colitis or primary sclerosing cholangitis. It may be useful in the differential diagnosis of Crohn's disease and ulcerative colitis and in the early diagnosis of ulcerative colitis. It also may be employed to distinguish primary biliary cirrhosis from primary sclerosing cholangitis.