Multicentre prospective study to evaluate effectiveness and safety of gel-forming and hyaluronic-acid containing chewable tablets as add-on treatment in patients with gastroesophageal reflux disease (GERD) symptoms and unsatisfying proton pump inhibitor therapy.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common disease which in the majority of patients is treated with proton pump inhibitors (PPI). However, up to 45% of the patients remain symptomatic on a standard dose of PPI. This study investigated the effectiveness and safety of an add-on therapy with the gel-forming chewable tablet Sobrade® in patients unsatisfied with PPI treatment. The bioadhesive gel covers the oesophagus and thereby protects the mucosa from reflux events. METHODS: 47 patients with symptomatic GERD despite PPI treatment participated in this study. The gel-forming tablets were taken up to four times daily after meals and prior to bedtime. Severity and frequency of GERD symptoms were evaluated during two onsite visits prior and following 14 days of treatment and used to calculate the GERD score of the Reflux Disease Questionnaire. Furthermore, patients recorded symptoms as well as onset and duration of symptoms relief daily in their electronic dairies. Effectiveness of treatment was analysed using non-parametric paired Wilcoxon test. In addition, anchor-based minimal important differences (MID) were assessed. RESULTS: Treatment resulted in significant reduction of GERD symptoms. Severity and frequency of 8 of the 9 assessed symptoms improved significantly during the treatment phase whereby most pronounced improvement was observed for heartburn. In agreement, all three subscales of the GERD score improved significantly. MID results suggest that patients considered a mean improvement of symptoms > 30% of initial severity as beneficial. Self-assessments by patients revealed first significant improvements of symptoms like heartburn and regurgitation from day 5 of treatment onwards. 49% of patients reported relief of symptoms within 15 min which lasted on average for 3.5 h. During the study no treatment emergent adverse events were reported and in 98% of all cases tolerability of the product was rated as very good or good. CONCLUSIONS: This study revealed a pronounced improvement of the symptoms after add-on treatment with the gel-forming medical device. The very good safety and tolerability profile indicate an advantageous risk-benefit ratio. TRIAL REGISTRATION: This non-interventional study was prospectively positively evaluated by the responsible ethic-committees.

Efficacy and safety of zapnometinib in hospitalised adult patients with COVID-19 (RESPIRE): a randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial.

Background: 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. Methods: 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). Findings: 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. Interpretation: 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. Funding: Atriva Therapeutics GmbH and the Federal Ministry of Education and Research, Germany.