Dataset Information

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.

SUBMITTER: Madan A

PROVIDER: S-EPMC6483311 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

Madan Anuradha A Chen Shuguang S Yates Phillip P Washburn Michael L ML Roberts Grace G Peat Andrew J AJ Tao Yu Y Parry Michael F MF Barnum Otis O McClain Micah T MT Roy-Ghanta Sumita S

Open forum infectious diseases 20190403 4

<h4>Background</h4>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.<h4>Methods</h4>In this phase 2b, double-blind, 3-arm study (NC ...[more]

PMID: 31041358

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Project description:ImportanceOseltamivir is recommended for all children hospitalized with influenza, despite limited evidence supporting its use in the inpatient setting.ObjectiveTo determine whether early oseltamivir use is associated with improved outcomes in children hospitalized with influenza.Design, setting, and participantsThis multicenter retrospective study included 55 799 children younger than 18 years who were hospitalized with influenza from October 1, 2007, to March 31, 2020, in 36 tertiary care pediatric hospitals who participate in the Pediatric Health Information System database. Data were analyzed from January 2021 to March 2022.ExposuresEarly oseltamivir treatment, defined as use of oseltamivir on hospital day 0 or 1.Main outcomes and measuresThe primary outcome was hospital length of stay (LOS) in calendar days. Secondary outcomes included 7-day hospital readmission, late (hospital day 2 or later) intensive care unit (ICU) transfer, and a composite outcome of in-hospital death or use of extracorporeal membrane oxygenation (ECMO). Inverse probability treatment weighting (IPTW) based on propensity scoring was used to address confounding by indication. Mixed-effects models were used to compare outcomes between children who did and did not receive early oseltamivir treatment. Outcomes were also compared within high-risk subgroups based on age, presence of a complex chronic condition, early critical illness, and history of asthma.ResultsThe analysis included 55 799 encounters from 36 hospitals. The median (IQR) age of the cohort was 3.61 years (1.03-8.27); 56% were male, and 44% were female. A total of 33 207 patients (59.5%) received early oseltamivir. In propensity score-weighted models, we found that children treated with early oseltamivir had shorter LOS (median 3 vs 4 days; IPTW model ratio, 0.52; 95% CI, 0.52-0.53) and lower odds of all-cause 7-day hospital readmission (3.5% vs 4.8%; adjusted odds ratio [aOR], 0.72; 95% CI, 0.66-0.77), late ICU transfer (2.4% vs 5.5%; aOR, 0.41; 95% CI, 0.37-0.46), and the composite outcome of death or ECMO use (0.9% vs 1.4%; aOR, 0.63; 95% CI, 0.54-0.73).Conclusions and relevanceEarly use of oseltamivir in hospitalized children was associated with shorter hospital stay and lower odds of 7-day readmission, ICU transfer, ECMO use, and death. These findings support the current recommendations for oseltamivir use in children hospitalized with influenza.

Project description:BackgroundInfluenza continues to have a substantial socioeconomic and health impact despite a long established vaccination programme and approved antivirals. Preclinical data suggest that combining antivirals might be more effective than administering oseltamivir alone in the treatment of influenza.MethodsWe did a randomised, double-blind, multicentre phase 2 trial of a combination of oseltamivir, amantadine, and ribavirin versus oseltamivir monotherapy with matching placebo for the treatment of influenza in 50 sites, consisting of academic medical centre clinics, emergency rooms, and private physician offices in the USA, Thailand, Mexico, Argentina, and Australia. Participants who were aged at least 18 years with influenza and were at increased risk of complications were randomly assigned (1:1) by an online computer-generated randomisation system to receive either oseltamivir (75 mg), amantadine (100 mg), and ribavirin (600 mg) combination therapy or oseltamivir monotherapy twice daily for 5 days, given orally, and participants were followed up for 28 days. Blinded treatment kits were used to achieve masking of patients and staff. The primary endpoint was the percentage of participants with virus detectable by PCR in nasopharyngeal swab at day 3, and was assessed in participants who were randomised, had influenza infection confirmed by the central laboratory on a baseline nasopharyngeal sample, and had received at least one dose of study drug. Safety assessment was done in all patients in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01227967.FindingsBetween March 1, 2011, and April 29, 2016, 633 participants were randomly assigned to receive combination antiviral therapy (n=316) or monotherapy (n=317). Seven participants were excluded from analysis: three were not properly randomised, three withdrew from the study, and one was lost to follow-up. The primary analysis included 394 participants, excluding 47 in the pilot phase, 172 without confirmed influenza, and 13 without an endpoint sample. 80 (40·0%) of 200 participants in the combination group had detectable virus at day 3 compared with 97 (50·0%) of 194 (mean difference 10·0, 95% CI 0·2-19·8, p=0·046) in the monotherapy group. The most common adverse events were gastrointestinal-related disorders, primarily nausea (65 [12%] of 556 reported adverse events in the combination group vs 63 [11%] of 585 reported adverse events in the monotherapy group), diarrhoea (56 [10%] of 556 vs 64 [11%] of 585), and vomiting (39 [7%] of 556 vs 23 [4%] of 585). There was no benefit in multiple clinical secondary endpoints, such as median duration of symptoms (4·5 days in the combination group vs 4·0 days in the monotherapy group; p=0·21). One death occurred in the study in an elderly participant in the monotherapy group who died of cardiovascular failure 13 days after randomisation, judged by the site investigator as not related to study intervention.InterpretationAlthough combination treatment showed a significant decrease in viral shedding at day 3 relative to monotherapy, this difference was not associated with improved clinical benefit. More work is needed to understand why there was no clinical benefit when a difference in virological outcome was identified.FundingNational Institute of Allergy and Infectious Diseases, National Institutes of Health, USA.

Project description:ImportanceOseltamivir therapy is recommended for all pediatric inpatients with influenza, particularly those with high-risk conditions, although data regarding its uptake and benefits are limited.ObjectiveTo describe temporal patterns and independent patient factors associated with the use of oseltamivir and explore patterns in resource use and patient outcomes among children hospitalized with influenza.Design, setting, and participantsThis multicenter retrospective cross-sectional study was conducted at 36 tertiary pediatric hospitals participating in the Pediatric Health Information System in the US. A total of 70 473 children younger than 18 years who were hospitalized with influenza between October 1, 2007, and March 31, 2020, were included.ExposuresHospitalization with a diagnosis of influenza.Main outcomes and measuresThe primary outcome was the use of oseltamivir, which was described by influenza season and by hospital. Patient factors associated with oseltamivir use were assessed using multivariable mixed-effects logistic regression models. Secondary outcomes were resource use (including antibiotic medications, chest radiography, supplemental oxygen, positive pressure ventilation, central venous catheter, and intensive care unit [ICU]) and patient outcomes (length of stay, late ICU transfer, 7-day hospital readmission, use of extracorporeal membrane oxygenation, and in-hospital mortality), which were described as percentages per influenza season.ResultsAmong 70 473 children hospitalized with influenza, the median (IQR) age was 3.65 (1.05-8.26) years; 30 750 patients (43.6%) were female, and 39 715 (56.4%) were male. Overall, 16 559 patients (23.5%) were Black, 36 184 (51.3%) were White, 14 133 (20.1%) were of other races (including 694 American Indian or Alaska Native [1.0%], 2216 Asian [3.0%], 372 Native Hawaiian or Pacific Islander [0.5%], and 10 850 other races [15.4%]), and 3597 (5.1%) were of unknown race. A total of 47 071 patients (66.8%) received oseltamivir, increasing from a low of 20.2% in the 2007-2008 influenza season to a high of 77.9% in the 2017-2018 season. Use by hospital ranged from 43.2% to 79.7% over the entire study period and from 56.5% to 90.1% in final influenza season studied (2019-2020). Factors associated with increased oseltamivir use included the presence of a complex chronic condition (odds ratio [OR], 1.42; 95% CI, 1.36-1.47), a history of asthma (OR, 1.31; 95% CI, 1.23-1.38), and early severe illness (OR, 1.19; 95% CI, 1.13-1.25). Children younger than 2 years (OR, 0.81; 95% CI, 0.77-0.85) and children aged 2 to 5 years (OR, 0.83; 95% CI, 0.79-0.88) had lower odds of receiving oseltamivir. From the beginning (2007-2008) to the end (2019-2020) of the study period, the use of antibiotic medications (from 74.4% to 60.1%) and chest radiography (from 59.2% to 51.7%) decreased, whereas the use of oxygen (from 33.6% to 29.3%), positive pressure ventilation (from 10.8% to 7.9%), and central venous catheters (from 2.5% to 1.0%) did not meaningfully change. Patient outcomes, including length of stay (median [IQR], 3 [2-5] days for all seasons), readmissions within 7 days (from 4.0% to 3.4%), use of extracorporeal membrane oxygenation (from 0.5% to 0.5%), and in-hospital mortality (from 1.1% to 0.8%), were stable from the beginning to the end of the study period.Conclusions and relevanceIn this cross-sectional study of children hospitalized with influenza, the use of oseltamivir increased over time, particularly among patients with high-risk conditions, but with wide institutional variation. Patient outcomes remained largely unchanged. Further work is needed to evaluate the impact of oseltamivir therapy in this population.

Dataset Information

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.

Background

Methods

Results

Conclusions

Clinical trial information

Publications

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.

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