GCP Service International Ltd & Co KG

Zapnometinib is an oral, non-ATP-competitive, small-molecule inhibitor of MEK1/MEK2 with immunomodulatory and antiviral properties. We aimed to investigate the safety and efficacy of zapnometinib in patients with COVID-19.

In this randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial, we recruited hospitalised adults with moderate or severe COVID-19 from 18 hospitals in Germany, India, Romania, South Africa, and Spain. Those requiring ICU admission or ventilator support at screening or randomisation were excluded. Patients were randomly assigned (1:1) to receive oral zapnometinib (900 mg on Day 1; 600 mg on Days 2-6) or matching placebo, on top of standard of care. Randomisation, stratified by baseline clinical severity status (CSS 3 or 4, measured on a 7-point ordinal scale), was done using Interactive Response Technology. Patients, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was CSS at Day 15 and was conducted on the full analysis set (FAS: all patients who were randomised to the study, received at least one dose of study medication and had at least one post-dose assessment of CSS, as randomised). Safety analyses were conducted on the safety analysis set (all study participants who received at least one dose of study medication, as treated). This study is registered at ClinicalTrials.gov (NCT04776044) and EudraCT (2020-004206-59).

The trial was terminated early as the emergence of the Omicron variant impacted recruitment. Between 12th April 2021 and 9th August 2022, 104 of the planned 220 patients were enrolled and randomly assigned, 103 were treated, and 101 were included in the FAS (zapnometinib: n = 50; placebo: n = 51). The primary outcome was not significantly different between the two groups, but patients on zapnometinib had higher odds of improved CSS versus placebo (odds ratio [OR] 1.54 [95% CI 0.72-3.33]; p = 0.26). Predefined subgroup analyses identified trends for improved CSS in patients with severe disease at baseline (OR 2.57 [0.76-8.88]; p = 0.13) and non-Omicron variants (OR 2.36 [0.85-6.71]; p = 0.10); the p value of the CSS subgroup by Treatment interaction term in the model was p = 0.28. The frequency and intensity of adverse events was low and similar between arms. Twenty (39.2%) patients treated with zapnometinib experienced adverse events compared with eighteen (34.6%) patients treated with placebo. One patient receiving zapnometinib and two patients receiving placebo died during the study. None of the deaths were considered related to study medication.

These results provide proof-of-concept for the innovative approach of targeting the Raf/MEK/ERK pathway in patients with hospitalised moderate/severe COVID-19. Further clinical studies will be required to evaluate the clinical benefit of zapnometinib in this and other indications.

Atriva Therapeutics GmbH and the Federal Ministry of Education and Research, Germany.

This prospective longitudinal epidemiological study was aimed at investigating the occupational SARS-CoV-2 infection risk of long distance train services in Germany. Three different employee groups (train attendants, train drivers and maintenance workers) within the workforce of the German railway carrier Deutsche Bahn Fernverkehr AG were studied based on their contact frequency with passengers and colleagues. Approximately 1100 employees were tested by PCR for acute infections and by antibody detection for past infections in June 2020, October 2020 and February 2021. Cumulative incidence (acute and past infections) after the third (final) test series in February 2021 was 8.5% (95% interval CI 6.8–10.4): 8.5% (95% CI 6.2–11.2) for train attendants, 5.5% (95% CI 2.9–9.5) for train drivers and 11.8% (95% CI 7.6–17.2) for maintenance workers. Between June 2020 and October 2020, the incidence was 1.2% (95% CI 0.6–2.3): 1.2% (95% CI 0.4–2.7) for train attendants, 1.1% (95% CI 0.1–3.9) for train drivers and 1.4% (95% CI 0.17–5.10) for maintenance workers. Between October 2020 and February 2021, it was 5.1% (95% CI 3.6–6.8): 5.2% (95% CI 3.3–7.8) for train attendants, 1.6% (95% CI 0.3–4.5) for train drivers and 8.8% (95% CI 4.9–14.3) for maintenance workers. Thus, contrary to expectation our exploratory data did not show train attendants to be at the highest risk of SARS-CoV-2 infections among the employee groups. In line with expectations, train drivers, representing the low contact group, seemed at lowest occupational risk.

Background: Allogeneic blood transfusions in oncologic surgery are associated with increased recurrence and mortality. Adverse effects on outcome could be reduced or avoided by using intraoperative autologous blood cell salvage (IOCS). However, there are concerns regarding the safety of the autologous IOCS blood. Previous meta-analyses from 2012 and 2020 did not identify increased risk of cancer recurrence after using autologous IOCS blood. The objective of this review was to reassess a greater number of IOCS-treated patients to present an updated and more robust analysis of the current literature. Methods: This systematic review includes full-text articles listed in PubMed, Cochrane, Cochrane Reviews, and Web of Science. We analyzed publications that discussed cell salvage or autotransfusion combined with the following outcomes: cancer recurrence, mortality, survival, allogeneic transfusion rate and requirements, length of hospital stay (LOS). To rate the strength of evidence, a Grading of Recommendations Assessment, Development and Evaluation (GRADE) of the underlying evidence was applied. Results: In the updated meta-analysis, 7 further observational studies were added to the original 27 observational studies included in the former 2020 analysis. Studies compared either unfiltered (n = 2,311) or filtered (n = 850) IOCS (total n = 3,161) versus non-IOCS use (n = 5,342). Control patients were either treated with autologous predonated blood (n = 484), with allogeneic transfusion (n = 4,113), or did not receive a blood transfusion (n = 745). However, the current literature still contains only observational studies on these topics, and the strength of evidence remains low. The risk of cancer recurrence was reduced in recipients of autologous salvaged blood with or without LDF (odds ratio [OR] 0.76, 95% confidence interval [CI]: 0.64–0.90) compared to nontransfused patients or patients with allogeneic transfusion. There was no difference in mortality (OR 0.95, 95% CI: 0.71–1.27) and LOS (mean difference −0.07 days, 95% CI: −0.63 to 0.48) between patients treated with IOCS blood or those in whom IOCS was not used. Due to high heterogeneity, transfusion rates or volumes could not be analyzed. Conclusion: Randomized controlled trials comparing mortality and cancer recurrence rate of IOCS with or without LDF filtration versus allogeneic blood transfusion were not found. Outcome was similar or better in patients receiving IOCS during cancer surgery compared to patients with allogeneic blood transfusion or nontransfused patients.