Efficacy and Safety of Danirixin (GSK1325756) Co-administered With Standard-of-Care Antiviral (Oseltamivir): A Phase 2b, Global, Randomized Study of Adults Hospitalized With Influenza

Abstract

Background: Excessive neutrophil migration has been correlated with influenza symptom severity. Danirixin (GSK1325756), a selective and reversible antagonist of C-X-C chemokine receptor 2, decreases neutrophil activation and transmigration to areas of inflammation. This study evaluated the efficacy and safety of intravenous (IV) danirixin co-administered with oseltamivir for the treatment of adults hospitalized with influenza.

Methods: In this phase 2b, double-blind, 3-arm study (NCT02927431), influenza-positive participants were randomized 2:2:1 to receive danirixin 15mg intravenously (IV) twice daily (bid) + oral oseltamivir 75mg bid (OSV), danirixin 50mg IV bid + OSV, or placebo IV bid + OSV, for up to 5 days. The primary endpoint was time to clinical response (TTCR).

Results: In total, 10 participants received study treatment (danirixin 15mg + OSV, n = 4; danirixin 50mg + OSV, n = 4; placebo + OSV, n = 2) before the study was terminated early due to low enrollment. All participants achieved a clinical response. Median (95% confidence interval) TTCR was 4.53 days (2.95, 5.71) for danirixin 15mg + OSV, 4.76 days (2.71, 5.25) for danirixin 50mg + OSV, and 1.33 days (0.71, 1.95) for placebo + OSV. Adverse events (AEs) were generally of mild or moderate intensity; no serious AEs were considered treatment-related. Interleukin-8 levels increased in nasal samples (using synthetic absorptive matrix strips) and decreased serum neutrophil-elastase-mediated degradation of elastin decreased in danirixin-treated participants, suggesting effective target engagement.

Conclusions: Interpretation of efficacy results is restricted by the low participant numbers. The safety and tolerability profile of danirixin was consistent with previous studies.

Clinical trial information: The registration data for the trial are in the ClinicalTrials.gov database, number NCT02927431, and in the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) as GSK study 201023, EudraCT 2016-002512-40. Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

Keywords: CXCR2 antagonist; danirixin; hospitalization; influenza; neutrophils.

Figures

Figure 1.

Study Design and Enrollment Cohorts. A, Study design. B, Participant enrollment and evaluation. Less severely ill hospitalized participants were defined as those with a hemodynamically stable status, requiring oxygenation with face mask, face tent, or nasal cannula, with or without radiological signs of lower respiratory tract disease or exacerbation of underlying chronic disease, including asthma, chronic obstructive pulmonary disease, or other cardiovascular conditions not leading to hemodynamic compromise. Critically ill hospitalized participants were defined as those requiring continuous positive airway pressure, bi-level positive airway pressure or mechanical ventilation, with hemodynamic instability (with or without pressor support) or illness with CNS involvement (eg, encephalopathy or encephalitis). CrCL indicates creatinine clearance; IDMC, Independent Data Monitoring Committee.

Figure 2.

Individual Plots of Nasal SAM Strips Biomarkers by Visit and Participant: (A) IL-8, (B) EL-NE and (C) IP-10. A, IL-8; B, EL-NE; C, IP-10. EL-NE indicates specific fragment human neutrophil elastase mediated degradation of elastin; IL-8, interleukin (IL)-8; IP-10, inducible protein-10.