Potential of FX06 to prevent disease progression in hospitalized non-intubated COVID-19 patients — the randomized, EU-wide, placebo-controlled, phase II study design of IXION
Authors: Kloka Jan , Friedrichson Benjamin , Dauth Stephanie , Foldenauer Ann Christina , Bulczak-Schadendorf Anita , Vehreschild Maria J. G. T. , Matos Francisco Maio , Riera-Mestre Antoni , van Asselt Antoinette D. I. , De Robertis Edoardo , Juskeviciene Vilma Traskaite , Meybohm Patrick , Tomescu Dana , Lacombe Karine , Stehouwer Coen D. A. , Zacharowski Kai ,   on behalf of the IXION Collaboration Group, Old Oliver , Ketomaeki Markus , Grebe Lea , Booms Patrick , Lindau Simone , Zinn Sebastian , Maushagen Isabel , Wolf Timo , Stephan Christoph , Weynants Cathy , Daamen Sylvia , Wülfroth Petra , Steiner Thomas , van Hulst Marinus , Kranke Peter , Hottenrott Sebastian , Schlesinger Tobias , Schmid Benedikt , Röder Daniel , Kranke Eva , Haas Tobias , Schlesinger Philipp , Sitter Magdalena , Valeri Davide , Iglesias Raquel Torres , Mora-Luján José María , Iriarte Adriana , Cerdà Pau , Vaguliene Neringa , Macas Andrius , Litviniene Jolanta , Balne Kristina , Monteiro Catarina , Ferreira Inês Antunes , Couceiro Patrícia , Soares Pedro , Beirão Sofia , Aad Yasmine Abi , Chiarabini Thibault , Popescu Mihai , van der Kallen C. J. H. 
Published: August 2022

Abstract
Background
More than 2.7 million hospitalizations of COVID-19-infected patients have occurred in Europe alone since the outbreak of the coronavirus in 2020. Interventions against SARS-CoV-2 are still in high need to prevent admissions to ICUs worldwide. FX06, a naturally occurring peptide in humans and other mammals, has the potential to reduce capillary leak by improving endothelial dysfunction and thus preventing the deterioration of patients. With IXION, we want to investigate the potential of FX06 to prevent disease progression in hospitalized, non-intubated COVID-19 patients.

Methods
IXION is an EU-wide, multicentre, placebo-controlled, double-blinded, parallel, randomized (2:1) phase II clinical study. Patient recruitment will start in September 2022 (to Q2/2023) in Germany, Italy, Lithuania, Spain, Romania, Portugal, and France. A total of 306 hospitalized patients (≥ 18 years and < 75 years) with a positive SARS-CoV-2 PCR test and a COVID-19 severity of 4–6 according to the WHO scale will be enrolled. After randomization to FX06 or placebo, patients will be assessed until day 28 (and followed up until day 60). FX06 (2 × 200 mg per day) or placebo will be administered intravenously for 5 consecutive days. The primary endpoint is to demonstrate a difference in the proportion of patients with progressed/worsened disease state in patients receiving FX06 compared to patients receiving placebo. Secondary endpoints are lung function, oxygen saturation and breathing rate, systemic inflammation, survival, capillary refill time, duration of hospital stay, and drug accountability.

Discussion
With IXION, the multidisciplinary consortium aims to deliver a new therapy in addition to standard care against SARS-CoV-2 for the clinical management of COVID-19 during mild and moderate stages. Potential limitations might refer to a lack of recruiting and drop-out due to various possible protocol violations. While we controlled for drop-outs in the same size estimation, recruitment problems may be subject to external problems difficult to control for.

Trial registration
EudraCT 2021-005059-35. Registered on 12 December 2021. Study Code TMP-2204-2021-47.