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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

Efficacy and Safety of Danirixin (GSK1325756) Co-administered with Standard-of-Care Antiviral... Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 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 1 1 2 1 3 Anuradha Madan, Shuguang Chen, Phillip Yates, Michael L Washburn, Grace Roberts, Andrew J 1 1 4 5 6 1 Peat, Yu Tao, Michael F Parry, Otis Barnum, Micah T. McClain, Sumita Roy-Ghanta 1 2 3 GlaxoSmithKline, Upper Providence, PA, USA; GlaxoSmithKline, Stevenage, UK; GlaxoSmithKline, 4 5 Research Triangle Park, NC, USA; Stamford Hospital, Stamford, CT, USA; Natchitoches Regional Medical Center, Natchitoches, LA, USA; Duke University Center for Applied Genomics & Precision Medicine, Durham, NC, USA Corresponding author: Dr Anuradha Madan GlaxoSmithKline, 1250 South Collegeville Road, Collegeville PA 19426, USA. Phone: +1 6109 174 030; Email: Anu.2.Madan@gsk.com Alternative corresponding author: Dr Phillip Yates GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK Phone: +44 143 876 2566; Email: phil.j.yates@gsk.com Clinical trial information: GSK study 201023, EudraCT 2016-002512-40, NCT02927431. Key Points In this phase 2b, randomized, placebo-controlled study of intravenous danirixin in hospitalized influenza patients, all participants achieved a clinical response; danirixin had an acceptable safety profile. Early termination due to low recruitment and small sample size limits interpretation. © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 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 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. Keywords Danirixin, CXCR2 antagonist, hospitalization, influenza, neutrophils Page 2 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 INTRODUCTION During the 2016–17 influenza season in the United States, a total of 18,184 laboratory-confirmed influenza-related hospitalizations were reported, with a cumulative incidence for all age groups of 65 per 100,000 population [1]. The investigation of novel treatments to reduce severity of disease and length of time spent in hospital, which in turn can reduce healthcare burden, is thus merited. One promising therapeutic approach is to target overactive and harmful aspects of the host response to influenza viruses. Following influenza virus infection, neutrophils are the most abundant cells that migrate to the lungs, and excessive migration has been demonstrated to cause lung damage through release of tissue-destructive enzymes and reactive oxygen species, and formation of neutrophil extracellular traps [2]. Levels of neutrophils and/or chemokines involved in neutrophil recruitment in the nasal or bronchoalveolar lavage fluid are correlated with clinical symptom severity of influenza infection in humans [3, 4]. Danirixin (GSK1325756) is a selective and reversible antagonist of the C-X-C chemokine receptor (CXCR2), which is expressed on the surface of neutrophils [5]. In preclinical studies, CXCR2 antagonism has been shown to decrease neutrophil activation and transmigration to areas of inflammation [6]. Phase 1 studies in healthy adults showed that danirixin was generally well tolerated at single doses up to 400 mg and with once-daily repeat dosing for 14 days at doses of 50 mg and 200 mg, all administered orally [7]. Oral danirixin has also been evaluated in a phase 2 outpatient study in adults with acute uncomplicated influenza, given either as monotherapy or in combination with the neuraminidase inhibitor, oseltamivir, a current standard-of-care antiviral therapy [8]. In addition to the phase 2 outpatient study, further phase 2 studies have been conducted (and are ongoing) in patients with chronic obstructive pulmonary disease (COPD), which have provided a sufficient body of evidence on the safety profile of danirixin, providing support for its evaluation in a critically ill population hospitalized with influenza [8, 9]. Page 3 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 The objective of the current study was to investigate the efficacy and safety of intravenous (IV) danirixin when co-administered with oral oseltamivir for the treatment of adults hospitalized with influenza. This is the first study in which hospitalized influenza patients were treated with IV danirixin. METHODS Study Design The Danirixin in Hospitalized Influenza (DAHLIA) study was a phase 2b, randomized, double-blind, placebo-controlled, 3-arm study of adult participants hospitalized with influenza (GSK study 201023, EudraCT 2016-002512-40, NCT02927431). Participants were randomized in a 2:2:1 ratio to receive danirixin 15 mg IV twice daily (bid) + oral oseltamivir 75 mg bid (hereafter referred to as the danirixin 15 mg + OSV group), danirixin 50 mg IV bid + oral oseltamivir 75 mg bid (the danirixin 50 mg + OSV group), or placebo IV bid + oral oseltamivir 75 mg bid (the placebo + OSV group). Treatment duration was up to 5 days, after which the investigator could elect to continue treatment with oral OSV. Follow-up continued until Day 45 for all participants (Figure 1A). Participants were enrolled in a stepwise manner, using three sentinel cohorts with increasing levels of renal impairment and disease severity, for enhanced safety monitoring (Figure 1B). The results from each cohort were to be reviewed by an Independent Data Monitoring Committee at regular intervals and before enrollment of subsequent sentinel cohorts. Participants were to be enrolled over three influenza seasons. However, the study was terminated after one season due to low enrollment. Written informed consent was obtained from each participant. The study was conducted in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practice, applicable country-specific requirements, and the Declaration of Helsinki. The study was approved by the appropriate Institutional Review Boards and Independent Ethics Committees. Page 4 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Randomization and Blinding Participants and site staff were blinded to danirixin and placebo, but OSV was given open-label in all treatment arms. Participants were assigned to study treatment in accordance with the randomization schedule generated by GlaxoSmithKline prior to the start of the study using validated internal software. Participant Population Eligible participants were required to have onset of influenza symptoms within 6 days prior to study enrollment, to have required hospitalization for treatment and supportive care for influenza, and to have tested positive for influenza by a next-generation rapid reverse transcriptase-polymerase chain reaction (RT-PCR) test, or other molecular-based assay. Additional eligibility criteria were as follows: age ≥18 years; presence of fever at baseline, indicated by ≥38.0°C/≥100.4°F, or history of fever during the prior 48 hours; oxygen saturation <95% on room air by transcutaneous method, or the need for supplemental oxygen or ventilator support, or increase in oxygen supplementation requirement of 2 liters for participants with chronic oxygen dependency, or an oxygen saturation of at least 3% below the participant’s historical baseline oxygen saturation for those with a history of chronic hypoxia (without supplemental oxygen). At least two of the following were also required: respiratory rate >24 breaths/min, heart rate >100 beats/min, systolic blood pressure (BP) <90 mm Hg. Baseline renal criteria were as shown in Figure 1B. Baseline liver function test eligibility criteria were bilirubin ≤2x upper limit of normal (ULN) with alanine aminotransferase (ALT) ≤5x ULN or ALT >5–≤8x ULN if bilirubin <1.5x ULN. Endpoints and Outcome Measures The primary endpoint was time to clinical response (TTCR), defined as hospital discharge due to clinical improvement or normalization of temperature and oxygen saturation (≥95%, without Page 5 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 supplemental oxygen), with 2 out of 3 of the following parameters also normalized: respiratory status (return to pre-morbid oxygen requirement in participants with chronic oxygen use, reversal of need for supplemental oxygen, or respiratory rate ≤24 breaths/min without supplemental oxygen); heart rate ≤100 beats/min; systolic BP ≥90 mmHg. Normalization of all these parameters had to be maintained for 24 hours or confirmed by hospital discharge. Key secondary endpoints included: time to respiratory response (TTRR), defined as a return to pre- morbid oxygen requirement (in participants with chronic oxygen use), a return to no requirement of supplemental oxygen, or a respiratory rate ≤24 breaths/min (without supplemental oxygen); clinical measures of influenza illness, including antibiotic use; safety and tolerability, including frequency of adverse events (AEs), serious AEs (SAEs), and change from baseline in clinical laboratory and electrocardiogram parameters. Key exploratory endpoints included change in influenza viral load, determined by quantitative RT-PCR, assessment of co-infection as determined by multiplex RT-PCR (BioFire Diagnostics, Salt Lake City, Utah, USA), and evaluation of biomarkers of inflammation and immune response, including but not limited to interleukin (IL)-8, inducible protein (IP)-10, myeloperoxidase, neutrophil elastase and matrix metalloprotease (MMP) degraded type I collagen (C1M), MMP-degraded type III collagen (C3M), specific fragment human neutrophil elastase mediated degradation of elastin (EL-NE), surfactant protein D (SP-D) and soluble receptor for advanced glycoprotein end product (sRAGE) from nasal samples or fluid, whole blood, bronchoalveolar lavage, and/or serum. The following samples were collected throughout the study: nasal swab samples, nasopharyngeal swab samples, nasal swab samples using synthetic absorptive matrix (SAM) strips (Hunt Developments [UK] Ltd, West Sussex, UK) and optional nasal washes, whole blood samples, serum, and bronchoalveolar lavage (BAL) samples from participants where part of routine management. Nasopharyngeal samples were used for diagnosis, subtyping, and quantification. Nasal swab samples Page 6 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 were used for diagnosis. BAL, nasal SAM strips and nasal wash samples were used for biomarker analysis. Statistical Methods Approximately 300 participants were planned to be enrolled in the study over three influenza seasons, with approximately 100 participants per season. This sample size was selected to achieve ≥80% overall power to detect a difference, under an assumption of a hazard ratio (HR) of 1.2 for danirixin 15 mg and 1.5 for danirixin 50 mg, and to retain a type I error <10% under the no-effect assumption. Analyses of participant disposition, baseline characteristics, and safety analyses used the Intent-to- Treat Exposed (ITT-E) and Safety populations, which consisted of all randomized participants who received ≥1 dose of investigational product. The Influenza-Positive (IP) population consisted of all participants in the ITT-E population with confirmed influenza infection and was used as the primary population for the primary endpoint and all other efficacy analyses. This study was terminated early with only a small number of participants treated, thus no formal hypothesis testing was performed. All analyses are descriptive and not intended for making definitive conclusions. Median TTCR in each treatment arm was determined from Kaplan–Meier (KM) analyses. Due to limited data, median TTRR could not be calculated for any of the treatment arms. Information on GSK’s data sharing commitments and requesting access can be found at https://www.clinicalstudydatarequest.com/. Page 7 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 RESULTS Study Population and Participant Disposition While the study was planned to take place across multiple sites in multiple countries (including France, the Netherlands, the Republic of Korea, Romania, the Russian Federation, Spain, Sweden, and the United States), participants were enrolled from 5 sites in the United States, and 1 each in Romania and Sweden, between January 19 and May 24, 2017 (the date of the last participant visit). Eleven participants were randomized into the study, of whom 10 received ≥1 dose of study medication; 1 participant was randomized but did not receive treatment owing to testing negative for influenza. All 10 participants were included in the ITT-E, IP, and Safety populations. Participant numbers for the three groups were as follows: danirixin 15 mg + OSV, n=4; danirixin 50 mg + OSV, n=4; placebo + OSV, n=2. Six participants completed the 5-day study treatment. Four participants received fewer than 5 days’ treatment because of clinical improvement, as determined by the investigator: 1 participant in the placebo + OSV arm was discharged from hospital on Day 2, and 3 participants in the danirixin + OSV arms were discharged from hospital on Days 4 or 5 (prior to the last danirixin bid dose). Of the 10 ITT-E participants, there was 1 withdrawal from the danirixin 50 mg + OSV treatment arm during follow-up because the participant withdrew consent on Day 15. None of the placebo participants had received OSV or steroids prior to study entry for influenza symptoms. One participant in the 15 mg OSV group and 2 in the 50 mg + OSV group received OSV as prior anti-influenza therapy and one participant each in the danirixin groups received steroids for their symptoms prior to study entry. Participants in the placebo group had fewer influenza symptoms at entry into the study whereas participant in the danirixin + OSV groups reported increased symptoms at study entry (Supplementary Table 1). Page 8 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Baseline demographic characteristics for the 10 participants were as follows: median (min, max) age was 68.5 (34, 90) years, 60% of participants were female, and the majority (70%) of participants were of white/Caucasian/European heritage. Time to Clinical Response All 10 (100%) participants in the IP population achieved a protocol-defined clinical response, with clinical improvement leading to discharge from hospital or vital sign resolution that was maintained for 24 hours. Median (95% confidence interval [CI]) TTCR by KM estimation was 4.53 (2.95, 5.71) days for danirixin 15 mg + OSV, 4.76 (2.71, 5.25) days for danirixin 50 mg + OSV, and 1.33 (0.71, 1.95) days for placebo + OSV (Table 1). Results for individual participants showed that 7 participants in the danirixin + OSV groups achieved TTCR between >2 and <6 days, and 2 participants in the placebo + OSV group achieved TTCR in ≤2 days. One participant in the danirixin 15 mg + OSV group achieved TTCR (vital sign resolution) at baseline after determination of eligibility and receiving the first dose (counted as achieving clinical response but not included in the KM estimate for TTCR). Time to Respiratory Response Five (50%) participants in the IP population achieved a protocol-defined respiratory response, with 50% of participants in all groups returning to no requirement for supplemental oxygen (Table 2). Clinical Measures of Influenza-Related Complications One participant from each treatment arm received concomitant antibiotics (benzylpenicillin sodium, ceftriaxone, or levofloxacin) for the treatment of influenza complications. Of these 3 participants, 1 received antibiotics starting 1 day before study Day 1, 1 participant starting on Day 1, and 1 participant starting on Day 2. One participant in the danirixin 50 mg + OSV group entered the study on mechanical ventilation due to a prior chronic condition and received bi-level positive airway pressure (BIPAP) on Day 20. A second participant, in the placebo + OSV group, received BIPAP on Day 2. Page 9 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Safety No AEs were reported for the 2 participants in the placebo + OSV arm. All participants in the danirixin + OSV treatment arms experienced 1 or more AE (Table 3), all of mild/Grade 1 or moderate/Grade 2 intensity. Laboratory assessments considered clinically significant by investigators were to be reported as AEs. No AEs of neutropenia were reported. One participant in the 50 mg danirixin +OSV group experienced neutropenia based on central laboratory results 3 days after end of treatment. The same participant reported a fungal infection, starting 2 days after the last dose of treatment, resolving in 4 days. This participant, who had a history of asthma, also reported bronchitis, which started 41 days after the last dose of treatment, and from which they were recovering at the end of the study (Day 45). This participant had one on-therapy AE of sinusitis on the second day of treatment, which resolved by Day 7. One participant in the danirixin 50 mg + OSV group experienced an AE of monocytosis, which started 6 days after start of study medication and was classed by the investigator to be possibly related to study medication. This participant, who entered the study with a history of tracheostomy for mechanical ventilation, Clostridium difficile infection, and oxygen supplementation also had recurrence of C. difficile infection post-treatment on Day 8 and Day 33. One participant receiving danirixin 15 mg + OSV reported an AE of bacterial pneumonia, 1 day after the last dose, which was considered neither serious nor related to treatment by study investigators. Two participants in the danirixin 50 mg + OSV treatment arm reported non-fatal SAEs considered by the investigators not to be related to study medication: aggravated heart failure in 1 participant with a history of heart failure and atrial fibrillation, and COPD exacerbation in the other participant. Both participants required hospital readmission on Day 8 for these conditions; both recovered and were discharged on Days 13 and 11, respectively. There were no fatal AEs or any AEs that led to withdrawal from the study or discontinuation of treatment. Page 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Exploratory Endpoints Virology Similar reductions in viral load occurred across all treatment arms (Supplementary Figure 1). All participants were infected with either influenza A or B virus and no participants were found to be co-infected with other viruses. Two neuraminidase resistance-associated substitutions (S245N and V149A) were detected in 7 and 1 participants, respectively, at baseline (prior to receipt of study medication). No participants harbored the most common neuraminidase OSV resistance substitution, H275Y. Biomarkers IL-8 levels increased in nasal SAM samples during treatment through Day 5 in danirixin + OSV treated participants and declined towards physiological baseline levels by Day 43-47. One placebo treated participant also had an increase in IL-8 and the other placebo treated participant had a high baseline level of IL-8 that was maintained over time (Figure 2a). No clear trends were observed in IL-8 nasal wash samples due to limited samples being collected. Lung damage associated biomarkers C1M, C3M, EL-NE, SP-D, and sRAGE were detectable in all matrixes analyzed. A trend of decreasing serum EL-NE in both danirixin + OSV-treated groups was observed (Figure 2b), indicating fewer neutrophil elastase driven lung elastin degradation events, but interpretation is limited due to the small participant population. No trends were observed, in the small set of biomarkers tested, between treatment arms for other lung damage associated biomarkers. High levels of IP-10 were observed at baseline, which declined over time (Figure 2c). DISCUSSION Of the 10 evaluable participants in this small phase 2b study, all 10 achieved a clinical response leading to hospital discharge or vital sign resolution that was maintained for 24 hours. Five of the Page 11 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 10 participants achieved a respiratory response with resolution of the need for supplemental oxygen. However, owing to the low number of participants enrolled, the conclusions that can be drawn from this participant population are limited. Recruitment challenges are common in studies of patients with influenza, primarily due to the short high-incidence periods and opportunistic enrollment [10]. Influenza activity during the 2016–2017 season was generally moderate in both the United States and Europe, where the study was conducted, suggesting that the mild nature of the influenza season may have contributed to the low participant numbers [1, 11]. As this was the first study in hospitalized patients receiving IV danirixin, eligibility criteria were relatively stringent with regards to concurrent conditions and medical history, but participants had to be severe enough to require hospitalization for their influenza. Following efforts to enroll participants for the entire season, only 10 participants met eligibility criteria and could be enrolled. While reasons for not enrolling subjects was not formally captured prospectively, information received from some investigators indicated that a large majority of potential participants did not meet eligibility criteria based on existing hospital records, which led to the conclusion that the probability of enrolling 300 participants in 2 more seasons would be very low. As such the decision was made to terminate the study. Current treatment guidelines for influenza requiring hospitalization recommend neuraminidase inhibitors as standard-of-care therapy, primarily oseltamivir and zanamivir [12]. However, the majority of clinical data for these antivirals come from outpatient studies of patients with mild, uncomplicated influenza [10]. Although observational studies have indicated that neuraminidase inhibitors may reduce severe clinical outcomes in patients hospitalized for influenza [13, 14], these findings have not been supported by clinical trials [15, 16], and as yet no treatment has been approved based on controlled studies in this population. Treatment of hospitalized patients presents multiple challenges, given the severity of disease and potential for complications, secondary infections, and requirement for intensive care [17]. Thus, there is a clear need for efficacious therapies in this high-risk group. Data from the phase 2 trials of danirixin, while affected by low Page 12 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 sample sizes, are therefore worthy of consideration, and further studies of this novel treatment are warranted. In the current study, while the primary outcome of TTCR was observed to be longer in the majority (n=7) of participants in the danirixin + OSV arms than in the 2 participants in the placebo + OSV arm, 10 participants form too small a group from which to draw conclusions. With such a small population, differences at baseline likely impacted study outcomes. For example, participants in the placebo + OSV group may have been less ill at study entry. A higher percentage in the danirixin arms had received prior oseltamivir and/or steroids as well as supplemental oxygen. Based on baseline characteristics, participants in the placebo group may have been less ill than in the danirixin groups at study entry. Although cross-trial comparisons should be interpreted with caution, a larger-scale phase 3 trial with over 600 participants hospitalized with influenza reported a median TTCR with placebo + OSV of 5.63 days, similar to that seen in the danirixin + OSV arms of this study [16]. IL-8 levels increased in nasal SAM samples in danirixin + OSV-treated participants which may be is indicative of target engagement, although variability and limited placebo samples for comparison prevent clear conclusions of the data. Interpretation of nasal wash analysis was hampered by the limited sample number, as samples were obtained from only 3 participants. Serum samples were taken for follow-up evaluation but were not tested for cytokines/chemokines due to the early termination of the study. This is in line with other clinical and preclinical studies suggesting IL-8 increase as an indicator of CXCR2 antagonism [18-20] [Washburn et al. co-submitted to OFID]. The trend of decreasing serum EL-NE in both danirixin + OSV treated groups in the current study, indicating fewer neutrophil-elastase driven lung elastin degradation events, but interpretation is again limited by the low participant numbers. The safety and tolerability of IV danirixin in our inpatient study was in line with the profile presented in outpatient studies in which danirixin was administered orally [8, 21]. One participant developed neutropenia three days post-treatment, based on laboratory results, and was not reported as an AE Page 13 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 by the investigator. The two SAEs in this inpatient study (aggravated cardiac failure and COPD exacerbation) were not considered by the investigators to be related to study treatment, and there were neither fatal AEs nor any AEs leading to study withdrawal or discontinuation. CONCLUSION While the potential for interpretation leading to general conclusions in this study was clearly restricted by the low number of participants, this small phase 2 study evaluating the efficacy and safety of IV danirixin in combination with oral OSV showed that all 10 influenza-positive participants achieved the primary endpoint of TTCR that enabled hospital discharge or the resolution of vital signs that were maintained for 24 hours. The study also showed danirixin to have a safety and tolerability profile congruous with that observed in other studies of this selective and reversible antagonist of CXCR2. Page 14 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Funding This work was supported by GlaxoSmithKline (GSK study number GSK201023). Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com. Acknowledgments The authors would like to thank the participants, investigators, and study staff for their contributions to this study. Heather St Michael, of Fishawack Indicia Ltd, UK, provided medical writing support, which was funded by GSK. Author Contributions AM, SR-G, SC, PY, MLW, AJP and GR were involved with the concept and design of the study and data analysis and interpretation. MFP, OB and MTM were involved with the concept and design of the study, patient recruitment and enrollment, and data acquisition. YT was involved in data analysis and interpretation. All authors were involved in the drafting, critical revision and approval of the article. Conflicts of Interest AM, SC, PY, MLW, GR, YT and SR-G are employees of GSK. AJP in an employee of GSK and has a patent WO2017093912 pending. MFP received compensation as a trial investigator from GSK. MTM received no other support from GSK outside the submitted work and has a patent pending on Biomarkers for the Molecular Classification of Viral and Bacterial Infection. OB report no conflicts of interest, aside from participation in this study. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Page 15 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 REFERENCES 1. Blanton L, Alabi N, Mustaquim D, et al. Update: Influenza Activity in the United States During the 2016–17 Season and Composition of the 2017–18 Influenza Vaccine. MMWR Morb Mortal Wkly Rep 2017; 66. 2. Narasaraju T, Yang E, Samy RP, et al. 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Miller BE, Mistry S, Smart K, et al. The pharmacokinetics and pharmacodynamics of danirixin (GSK1325756) − a selective CXCR2 antagonist − in healthy adult subjects. BMC Pharmacology and Toxicology 2015; 16:18. 8. Roberts G, Chen S, Yates P, et al. Tandomized, Double-Blind, Placebo-Controlled Study of the Safety, Tolerability and Clinical Effect of Danirixin i)n Adults with Acute, Uncomplicated Influenza. OFID (accepted for publication, OFID-D 18-0069) 9. Lazaar AL, Miller BE, Tabberer M, et al. Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD. European Respiratory Journal 2018. Page 16 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 10. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, and Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348:g2545. 11. European Centre for Disease Prevention and Control. Influenza in Europe, Season 2016– 2017. 2017 [cited 2018 February 28]; Available from: https://ecdc.europa.eu/en/publications- data/influenza-europe-season-2016-2017. 12. Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011; 60:1-24. 13. McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis 2007; 45:1568-75. 14. Lee N, Choi KW, Chan PK, et al. Outcomes of adults hospitalised with severe influenza. Thorax 2010; 65:510-5. 15. de Jong MD, Ison MG, Monto AS, et al. Evaluation of intravenous peramivir for treatment of influenza in hospitalized patients. Clin Infect Dis 2014; 59:e172-85. 16. Marty FM, Vidal-Puigserver J, Clark C, et al. Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. Lancet Respir Med 2017; 5:135-146. 17. Garg S, Jain S, Dawood FS, et al. Pneumonia among adults hospitalized with laboratory- confirmed seasonal influenza virus infection-United States, 2005-2008. BMC Infect Dis 2015; 15:369. 18. Jurcevic S, Humfrey C, Uddin M, Warrington S, Larsson B, and Keen C. The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions. Br J Clin Pharmacol 2015; 80:1324-36. 19. Moss RB, Mistry SJ, Konstan MW, et al. Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J Cyst Fibros 2013; 12:241-8. Page 17 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 20. Thatcher TH, McHugh NA, Egan RW, et al. Role of CXCR2 in cigarette smoke-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol 2005; 289:L322-8. 21. Miller BE, Smart K, Mistry S, et al. The pharmacokinetics of conventional and bioenhanced tablet formulations of danirixin (GSK1325756) following oral administration in healthy, elderly, human volunteers. Eur J Drug Metab Pharmacokinet 2014; 39:173-81. Page 18 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 TABLES AND FIGURES Table 1. Clinical Response in the Influenza Positive Population Placebo + Danirixin Danirixin oseltamivir 15 mg + 50 mg + 75 mg (n=2) oseltamivir oseltamivir a b 75 mg (n=4) 75 mg (n=4) Clinical Response, n 2 4 4 Yes, n (%) 2 (100) 4 (100) 4 (100) Hospital discharge due to clinical 0 1 (25) 2 (50) improvement, n (%) Hospital discharge as 24-hr 1 (50) 2 (50) 1 (25) confirmation, n (%) Vital signs resolved, n (%) 1 (50) 1 (25) 1 (25) Clinical Outcome, n 2 4 4 Clinical improvement, n (%) 2 (100) 4 (100) 4 (100) Kaplan–Meier Estimate, n 2 3 4 Median, days 1.33 4.53 4.76 95% confidence interval 0.71, 1.95 2.95, 5.71 2.71, 5.25 25%–75% 0.71–1.95 2.95–5.71 3.66–5.08 One participant in the danirixin 15 mg + oseltamivir 75 mg group had vital sign resolution at baseline and was counted as having a clinical response but was not included in the Kaplan–Meier estimates. One participant in the danirixin 50 mg + oseltamivir 75 mg group received oseltamivir 30 mg. Hospital discharge due to clinical improvement served as 24-hour confirmation for the clinical response. Page 19 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Table 2. Respiratory Response in the Influenza Positive Population Placebo + Danirixin Danirixin oseltamivir 15 mg + 50 mg + 75 mg (n=2) oseltamivir oseltamivir 75 mg (n=4) 75 mg (n=4) Positive Respiratory Response, n 2 4 4 Yes, n (%) 1 (50) 2 (50) 2 (50) Respiratory rate ≤24/min 0 0 0 (without supplemental oxygen) Return to no requirement of supplemental 1 (50) 2 (50) 2 (50) oxygen, n (%) Return to pre-morbid oxygen 0 0 0 (participants with chronic oxygen use) One participant in the danirixin 50 mg + oseltamivir 75 mg group received oseltamivir 30 mg. Page 20 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Table 3. Adverse Events Reported by Overall Frequency in the Safety Population Preferred Term Placebo + Danirixin Danirixin Total oseltamivir 15 mg + 50 mg + (N=10) 75 mg (n=2) oseltamivir oseltamivir 75 mg (n=4) 75 mg (n=4) Any event, n (%) 0 4 (100) 4 (100) 8 (80) Asthma 0 1 (25) 0 1 (10) Atelectasis 0 0 1 (25) 1 (10) Bronchitis 0 0 1 (25) 1 (10) Cardiac failure 0 0 1 (25) 1 (10) Chills 0 0 1 (25) 1 (10) COPD 0 0 1 (25) 1 (10) Clostridium difficile infection 0 0 1 (25) 1 (10) Contusion 0 1 (25) 0 1 (10) Cough 0 1 (25) 0 1 (10) Dyspnea 0 0 1 (25) 1 (10) Fungal infection 0 0 1 (25) 1 (10) Hemoglobin decreased 0 0 1 (25) 1 (10) Hyperglycemia 0 1 (25) 0 1 (10) Hypokalemia 0 0 1 (25) 1 (10) Infusion-site extravasation 0 0 1 (25) 1 (10) Monocytosis 0 0 1 (25) 1 (10) Pneumonia bacterial 0 1 (25) 0 1 (10) Sinusitis 0 0 1 (25) 1 (10) Vertigo 0 1 (25) 0 1 (10) One participant in the danirixin 50 mg + oseltamivir 75 mg group received oseltamivir 30 mg. COPD, chronic obstructive pulmonary disease. Page 21 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Figure Legend Figure 1. (A) Study Design and (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, encephalitis). CrCL, 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 B C D EL-NE, specific fragment human neutrophil elastase mediated degradation of elastin, IL8, interleukin (IL)-8; IP10, inducible protein (IP)-10 Page 22 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Figure 1 Page 23 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Figure 2 Page 24 Accepted Manuscript http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

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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Abstract

Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 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 1 1 2 1 3 Anuradha Madan, Shuguang Chen, Phillip Yates, Michael L Washburn, Grace Roberts, Andrew J 1 1 4 5 6 1 Peat, Yu Tao, Michael F Parry, Otis Barnum, Micah T. McClain, Sumita Roy-Ghanta 1 2 3 GlaxoSmithKline, Upper Providence, PA, USA; GlaxoSmithKline, Stevenage, UK; GlaxoSmithKline, 4 5 Research Triangle Park, NC, USA; Stamford Hospital, Stamford, CT, USA; Natchitoches Regional Medical Center, Natchitoches, LA, USA; Duke University Center for Applied Genomics & Precision Medicine, Durham, NC, USA Corresponding author: Dr Anuradha Madan GlaxoSmithKline, 1250 South Collegeville Road, Collegeville PA 19426, USA. Phone: +1 6109 174 030; Email: Anu.2.Madan@gsk.com Alternative corresponding author: Dr Phillip Yates GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK Phone: +44 143 876 2566; Email: phil.j.yates@gsk.com Clinical trial information: GSK study 201023, EudraCT 2016-002512-40, NCT02927431. Key Points In this phase 2b, randomized, placebo-controlled study of intravenous danirixin in hospitalized influenza patients, all participants achieved a clinical response; danirixin had an acceptable safety profile. Early termination due to low recruitment and small sample size limits interpretation. © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 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 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. Keywords Danirixin, CXCR2 antagonist, hospitalization, influenza, neutrophils Page 2 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 INTRODUCTION During the 2016–17 influenza season in the United States, a total of 18,184 laboratory-confirmed influenza-related hospitalizations were reported, with a cumulative incidence for all age groups of 65 per 100,000 population [1]. The investigation of novel treatments to reduce severity of disease and length of time spent in hospital, which in turn can reduce healthcare burden, is thus merited. One promising therapeutic approach is to target overactive and harmful aspects of the host response to influenza viruses. Following influenza virus infection, neutrophils are the most abundant cells that migrate to the lungs, and excessive migration has been demonstrated to cause lung damage through release of tissue-destructive enzymes and reactive oxygen species, and formation of neutrophil extracellular traps [2]. Levels of neutrophils and/or chemokines involved in neutrophil recruitment in the nasal or bronchoalveolar lavage fluid are correlated with clinical symptom severity of influenza infection in humans [3, 4]. Danirixin (GSK1325756) is a selective and reversible antagonist of the C-X-C chemokine receptor (CXCR2), which is expressed on the surface of neutrophils [5]. In preclinical studies, CXCR2 antagonism has been shown to decrease neutrophil activation and transmigration to areas of inflammation [6]. Phase 1 studies in healthy adults showed that danirixin was generally well tolerated at single doses up to 400 mg and with once-daily repeat dosing for 14 days at doses of 50 mg and 200 mg, all administered orally [7]. Oral danirixin has also been evaluated in a phase 2 outpatient study in adults with acute uncomplicated influenza, given either as monotherapy or in combination with the neuraminidase inhibitor, oseltamivir, a current standard-of-care antiviral therapy [8]. In addition to the phase 2 outpatient study, further phase 2 studies have been conducted (and are ongoing) in patients with chronic obstructive pulmonary disease (COPD), which have provided a sufficient body of evidence on the safety profile of danirixin, providing support for its evaluation in a critically ill population hospitalized with influenza [8, 9]. Page 3 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 The objective of the current study was to investigate the efficacy and safety of intravenous (IV) danirixin when co-administered with oral oseltamivir for the treatment of adults hospitalized with influenza. This is the first study in which hospitalized influenza patients were treated with IV danirixin. METHODS Study Design The Danirixin in Hospitalized Influenza (DAHLIA) study was a phase 2b, randomized, double-blind, placebo-controlled, 3-arm study of adult participants hospitalized with influenza (GSK study 201023, EudraCT 2016-002512-40, NCT02927431). Participants were randomized in a 2:2:1 ratio to receive danirixin 15 mg IV twice daily (bid) + oral oseltamivir 75 mg bid (hereafter referred to as the danirixin 15 mg + OSV group), danirixin 50 mg IV bid + oral oseltamivir 75 mg bid (the danirixin 50 mg + OSV group), or placebo IV bid + oral oseltamivir 75 mg bid (the placebo + OSV group). Treatment duration was up to 5 days, after which the investigator could elect to continue treatment with oral OSV. Follow-up continued until Day 45 for all participants (Figure 1A). Participants were enrolled in a stepwise manner, using three sentinel cohorts with increasing levels of renal impairment and disease severity, for enhanced safety monitoring (Figure 1B). The results from each cohort were to be reviewed by an Independent Data Monitoring Committee at regular intervals and before enrollment of subsequent sentinel cohorts. Participants were to be enrolled over three influenza seasons. However, the study was terminated after one season due to low enrollment. Written informed consent was obtained from each participant. The study was conducted in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practice, applicable country-specific requirements, and the Declaration of Helsinki. The study was approved by the appropriate Institutional Review Boards and Independent Ethics Committees. Page 4 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Randomization and Blinding Participants and site staff were blinded to danirixin and placebo, but OSV was given open-label in all treatment arms. Participants were assigned to study treatment in accordance with the randomization schedule generated by GlaxoSmithKline prior to the start of the study using validated internal software. Participant Population Eligible participants were required to have onset of influenza symptoms within 6 days prior to study enrollment, to have required hospitalization for treatment and supportive care for influenza, and to have tested positive for influenza by a next-generation rapid reverse transcriptase-polymerase chain reaction (RT-PCR) test, or other molecular-based assay. Additional eligibility criteria were as follows: age ≥18 years; presence of fever at baseline, indicated by ≥38.0°C/≥100.4°F, or history of fever during the prior 48 hours; oxygen saturation <95% on room air by transcutaneous method, or the need for supplemental oxygen or ventilator support, or increase in oxygen supplementation requirement of 2 liters for participants with chronic oxygen dependency, or an oxygen saturation of at least 3% below the participant’s historical baseline oxygen saturation for those with a history of chronic hypoxia (without supplemental oxygen). At least two of the following were also required: respiratory rate >24 breaths/min, heart rate >100 beats/min, systolic blood pressure (BP) <90 mm Hg. Baseline renal criteria were as shown in Figure 1B. Baseline liver function test eligibility criteria were bilirubin ≤2x upper limit of normal (ULN) with alanine aminotransferase (ALT) ≤5x ULN or ALT >5–≤8x ULN if bilirubin <1.5x ULN. Endpoints and Outcome Measures The primary endpoint was time to clinical response (TTCR), defined as hospital discharge due to clinical improvement or normalization of temperature and oxygen saturation (≥95%, without Page 5 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 supplemental oxygen), with 2 out of 3 of the following parameters also normalized: respiratory status (return to pre-morbid oxygen requirement in participants with chronic oxygen use, reversal of need for supplemental oxygen, or respiratory rate ≤24 breaths/min without supplemental oxygen); heart rate ≤100 beats/min; systolic BP ≥90 mmHg. Normalization of all these parameters had to be maintained for 24 hours or confirmed by hospital discharge. Key secondary endpoints included: time to respiratory response (TTRR), defined as a return to pre- morbid oxygen requirement (in participants with chronic oxygen use), a return to no requirement of supplemental oxygen, or a respiratory rate ≤24 breaths/min (without supplemental oxygen); clinical measures of influenza illness, including antibiotic use; safety and tolerability, including frequency of adverse events (AEs), serious AEs (SAEs), and change from baseline in clinical laboratory and electrocardiogram parameters. Key exploratory endpoints included change in influenza viral load, determined by quantitative RT-PCR, assessment of co-infection as determined by multiplex RT-PCR (BioFire Diagnostics, Salt Lake City, Utah, USA), and evaluation of biomarkers of inflammation and immune response, including but not limited to interleukin (IL)-8, inducible protein (IP)-10, myeloperoxidase, neutrophil elastase and matrix metalloprotease (MMP) degraded type I collagen (C1M), MMP-degraded type III collagen (C3M), specific fragment human neutrophil elastase mediated degradation of elastin (EL-NE), surfactant protein D (SP-D) and soluble receptor for advanced glycoprotein end product (sRAGE) from nasal samples or fluid, whole blood, bronchoalveolar lavage, and/or serum. The following samples were collected throughout the study: nasal swab samples, nasopharyngeal swab samples, nasal swab samples using synthetic absorptive matrix (SAM) strips (Hunt Developments [UK] Ltd, West Sussex, UK) and optional nasal washes, whole blood samples, serum, and bronchoalveolar lavage (BAL) samples from participants where part of routine management. Nasopharyngeal samples were used for diagnosis, subtyping, and quantification. Nasal swab samples Page 6 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 were used for diagnosis. BAL, nasal SAM strips and nasal wash samples were used for biomarker analysis. Statistical Methods Approximately 300 participants were planned to be enrolled in the study over three influenza seasons, with approximately 100 participants per season. This sample size was selected to achieve ≥80% overall power to detect a difference, under an assumption of a hazard ratio (HR) of 1.2 for danirixin 15 mg and 1.5 for danirixin 50 mg, and to retain a type I error <10% under the no-effect assumption. Analyses of participant disposition, baseline characteristics, and safety analyses used the Intent-to- Treat Exposed (ITT-E) and Safety populations, which consisted of all randomized participants who received ≥1 dose of investigational product. The Influenza-Positive (IP) population consisted of all participants in the ITT-E population with confirmed influenza infection and was used as the primary population for the primary endpoint and all other efficacy analyses. This study was terminated early with only a small number of participants treated, thus no formal hypothesis testing was performed. All analyses are descriptive and not intended for making definitive conclusions. Median TTCR in each treatment arm was determined from Kaplan–Meier (KM) analyses. Due to limited data, median TTRR could not be calculated for any of the treatment arms. Information on GSK’s data sharing commitments and requesting access can be found at https://www.clinicalstudydatarequest.com/. Page 7 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 RESULTS Study Population and Participant Disposition While the study was planned to take place across multiple sites in multiple countries (including France, the Netherlands, the Republic of Korea, Romania, the Russian Federation, Spain, Sweden, and the United States), participants were enrolled from 5 sites in the United States, and 1 each in Romania and Sweden, between January 19 and May 24, 2017 (the date of the last participant visit). Eleven participants were randomized into the study, of whom 10 received ≥1 dose of study medication; 1 participant was randomized but did not receive treatment owing to testing negative for influenza. All 10 participants were included in the ITT-E, IP, and Safety populations. Participant numbers for the three groups were as follows: danirixin 15 mg + OSV, n=4; danirixin 50 mg + OSV, n=4; placebo + OSV, n=2. Six participants completed the 5-day study treatment. Four participants received fewer than 5 days’ treatment because of clinical improvement, as determined by the investigator: 1 participant in the placebo + OSV arm was discharged from hospital on Day 2, and 3 participants in the danirixin + OSV arms were discharged from hospital on Days 4 or 5 (prior to the last danirixin bid dose). Of the 10 ITT-E participants, there was 1 withdrawal from the danirixin 50 mg + OSV treatment arm during follow-up because the participant withdrew consent on Day 15. None of the placebo participants had received OSV or steroids prior to study entry for influenza symptoms. One participant in the 15 mg OSV group and 2 in the 50 mg + OSV group received OSV as prior anti-influenza therapy and one participant each in the danirixin groups received steroids for their symptoms prior to study entry. Participants in the placebo group had fewer influenza symptoms at entry into the study whereas participant in the danirixin + OSV groups reported increased symptoms at study entry (Supplementary Table 1). Page 8 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Baseline demographic characteristics for the 10 participants were as follows: median (min, max) age was 68.5 (34, 90) years, 60% of participants were female, and the majority (70%) of participants were of white/Caucasian/European heritage. Time to Clinical Response All 10 (100%) participants in the IP population achieved a protocol-defined clinical response, with clinical improvement leading to discharge from hospital or vital sign resolution that was maintained for 24 hours. Median (95% confidence interval [CI]) TTCR by KM estimation was 4.53 (2.95, 5.71) days for danirixin 15 mg + OSV, 4.76 (2.71, 5.25) days for danirixin 50 mg + OSV, and 1.33 (0.71, 1.95) days for placebo + OSV (Table 1). Results for individual participants showed that 7 participants in the danirixin + OSV groups achieved TTCR between >2 and <6 days, and 2 participants in the placebo + OSV group achieved TTCR in ≤2 days. One participant in the danirixin 15 mg + OSV group achieved TTCR (vital sign resolution) at baseline after determination of eligibility and receiving the first dose (counted as achieving clinical response but not included in the KM estimate for TTCR). Time to Respiratory Response Five (50%) participants in the IP population achieved a protocol-defined respiratory response, with 50% of participants in all groups returning to no requirement for supplemental oxygen (Table 2). Clinical Measures of Influenza-Related Complications One participant from each treatment arm received concomitant antibiotics (benzylpenicillin sodium, ceftriaxone, or levofloxacin) for the treatment of influenza complications. Of these 3 participants, 1 received antibiotics starting 1 day before study Day 1, 1 participant starting on Day 1, and 1 participant starting on Day 2. One participant in the danirixin 50 mg + OSV group entered the study on mechanical ventilation due to a prior chronic condition and received bi-level positive airway pressure (BIPAP) on Day 20. A second participant, in the placebo + OSV group, received BIPAP on Day 2. Page 9 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Safety No AEs were reported for the 2 participants in the placebo + OSV arm. All participants in the danirixin + OSV treatment arms experienced 1 or more AE (Table 3), all of mild/Grade 1 or moderate/Grade 2 intensity. Laboratory assessments considered clinically significant by investigators were to be reported as AEs. No AEs of neutropenia were reported. One participant in the 50 mg danirixin +OSV group experienced neutropenia based on central laboratory results 3 days after end of treatment. The same participant reported a fungal infection, starting 2 days after the last dose of treatment, resolving in 4 days. This participant, who had a history of asthma, also reported bronchitis, which started 41 days after the last dose of treatment, and from which they were recovering at the end of the study (Day 45). This participant had one on-therapy AE of sinusitis on the second day of treatment, which resolved by Day 7. One participant in the danirixin 50 mg + OSV group experienced an AE of monocytosis, which started 6 days after start of study medication and was classed by the investigator to be possibly related to study medication. This participant, who entered the study with a history of tracheostomy for mechanical ventilation, Clostridium difficile infection, and oxygen supplementation also had recurrence of C. difficile infection post-treatment on Day 8 and Day 33. One participant receiving danirixin 15 mg + OSV reported an AE of bacterial pneumonia, 1 day after the last dose, which was considered neither serious nor related to treatment by study investigators. Two participants in the danirixin 50 mg + OSV treatment arm reported non-fatal SAEs considered by the investigators not to be related to study medication: aggravated heart failure in 1 participant with a history of heart failure and atrial fibrillation, and COPD exacerbation in the other participant. Both participants required hospital readmission on Day 8 for these conditions; both recovered and were discharged on Days 13 and 11, respectively. There were no fatal AEs or any AEs that led to withdrawal from the study or discontinuation of treatment. Page 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Exploratory Endpoints Virology Similar reductions in viral load occurred across all treatment arms (Supplementary Figure 1). All participants were infected with either influenza A or B virus and no participants were found to be co-infected with other viruses. Two neuraminidase resistance-associated substitutions (S245N and V149A) were detected in 7 and 1 participants, respectively, at baseline (prior to receipt of study medication). No participants harbored the most common neuraminidase OSV resistance substitution, H275Y. Biomarkers IL-8 levels increased in nasal SAM samples during treatment through Day 5 in danirixin + OSV treated participants and declined towards physiological baseline levels by Day 43-47. One placebo treated participant also had an increase in IL-8 and the other placebo treated participant had a high baseline level of IL-8 that was maintained over time (Figure 2a). No clear trends were observed in IL-8 nasal wash samples due to limited samples being collected. Lung damage associated biomarkers C1M, C3M, EL-NE, SP-D, and sRAGE were detectable in all matrixes analyzed. A trend of decreasing serum EL-NE in both danirixin + OSV-treated groups was observed (Figure 2b), indicating fewer neutrophil elastase driven lung elastin degradation events, but interpretation is limited due to the small participant population. No trends were observed, in the small set of biomarkers tested, between treatment arms for other lung damage associated biomarkers. High levels of IP-10 were observed at baseline, which declined over time (Figure 2c). DISCUSSION Of the 10 evaluable participants in this small phase 2b study, all 10 achieved a clinical response leading to hospital discharge or vital sign resolution that was maintained for 24 hours. Five of the Page 11 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 10 participants achieved a respiratory response with resolution of the need for supplemental oxygen. However, owing to the low number of participants enrolled, the conclusions that can be drawn from this participant population are limited. Recruitment challenges are common in studies of patients with influenza, primarily due to the short high-incidence periods and opportunistic enrollment [10]. Influenza activity during the 2016–2017 season was generally moderate in both the United States and Europe, where the study was conducted, suggesting that the mild nature of the influenza season may have contributed to the low participant numbers [1, 11]. As this was the first study in hospitalized patients receiving IV danirixin, eligibility criteria were relatively stringent with regards to concurrent conditions and medical history, but participants had to be severe enough to require hospitalization for their influenza. Following efforts to enroll participants for the entire season, only 10 participants met eligibility criteria and could be enrolled. While reasons for not enrolling subjects was not formally captured prospectively, information received from some investigators indicated that a large majority of potential participants did not meet eligibility criteria based on existing hospital records, which led to the conclusion that the probability of enrolling 300 participants in 2 more seasons would be very low. As such the decision was made to terminate the study. Current treatment guidelines for influenza requiring hospitalization recommend neuraminidase inhibitors as standard-of-care therapy, primarily oseltamivir and zanamivir [12]. However, the majority of clinical data for these antivirals come from outpatient studies of patients with mild, uncomplicated influenza [10]. Although observational studies have indicated that neuraminidase inhibitors may reduce severe clinical outcomes in patients hospitalized for influenza [13, 14], these findings have not been supported by clinical trials [15, 16], and as yet no treatment has been approved based on controlled studies in this population. Treatment of hospitalized patients presents multiple challenges, given the severity of disease and potential for complications, secondary infections, and requirement for intensive care [17]. Thus, there is a clear need for efficacious therapies in this high-risk group. Data from the phase 2 trials of danirixin, while affected by low Page 12 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 sample sizes, are therefore worthy of consideration, and further studies of this novel treatment are warranted. In the current study, while the primary outcome of TTCR was observed to be longer in the majority (n=7) of participants in the danirixin + OSV arms than in the 2 participants in the placebo + OSV arm, 10 participants form too small a group from which to draw conclusions. With such a small population, differences at baseline likely impacted study outcomes. For example, participants in the placebo + OSV group may have been less ill at study entry. A higher percentage in the danirixin arms had received prior oseltamivir and/or steroids as well as supplemental oxygen. Based on baseline characteristics, participants in the placebo group may have been less ill than in the danirixin groups at study entry. Although cross-trial comparisons should be interpreted with caution, a larger-scale phase 3 trial with over 600 participants hospitalized with influenza reported a median TTCR with placebo + OSV of 5.63 days, similar to that seen in the danirixin + OSV arms of this study [16]. IL-8 levels increased in nasal SAM samples in danirixin + OSV-treated participants which may be is indicative of target engagement, although variability and limited placebo samples for comparison prevent clear conclusions of the data. Interpretation of nasal wash analysis was hampered by the limited sample number, as samples were obtained from only 3 participants. Serum samples were taken for follow-up evaluation but were not tested for cytokines/chemokines due to the early termination of the study. This is in line with other clinical and preclinical studies suggesting IL-8 increase as an indicator of CXCR2 antagonism [18-20] [Washburn et al. co-submitted to OFID]. The trend of decreasing serum EL-NE in both danirixin + OSV treated groups in the current study, indicating fewer neutrophil-elastase driven lung elastin degradation events, but interpretation is again limited by the low participant numbers. The safety and tolerability of IV danirixin in our inpatient study was in line with the profile presented in outpatient studies in which danirixin was administered orally [8, 21]. One participant developed neutropenia three days post-treatment, based on laboratory results, and was not reported as an AE Page 13 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 by the investigator. The two SAEs in this inpatient study (aggravated cardiac failure and COPD exacerbation) were not considered by the investigators to be related to study treatment, and there were neither fatal AEs nor any AEs leading to study withdrawal or discontinuation. CONCLUSION While the potential for interpretation leading to general conclusions in this study was clearly restricted by the low number of participants, this small phase 2 study evaluating the efficacy and safety of IV danirixin in combination with oral OSV showed that all 10 influenza-positive participants achieved the primary endpoint of TTCR that enabled hospital discharge or the resolution of vital signs that were maintained for 24 hours. The study also showed danirixin to have a safety and tolerability profile congruous with that observed in other studies of this selective and reversible antagonist of CXCR2. Page 14 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Funding This work was supported by GlaxoSmithKline (GSK study number GSK201023). Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com. Acknowledgments The authors would like to thank the participants, investigators, and study staff for their contributions to this study. Heather St Michael, of Fishawack Indicia Ltd, UK, provided medical writing support, which was funded by GSK. Author Contributions AM, SR-G, SC, PY, MLW, AJP and GR were involved with the concept and design of the study and data analysis and interpretation. MFP, OB and MTM were involved with the concept and design of the study, patient recruitment and enrollment, and data acquisition. YT was involved in data analysis and interpretation. All authors were involved in the drafting, critical revision and approval of the article. Conflicts of Interest AM, SC, PY, MLW, GR, YT and SR-G are employees of GSK. AJP in an employee of GSK and has a patent WO2017093912 pending. MFP received compensation as a trial investigator from GSK. MTM received no other support from GSK outside the submitted work and has a patent pending on Biomarkers for the Molecular Classification of Viral and Bacterial Infection. OB report no conflicts of interest, aside from participation in this study. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Page 15 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 REFERENCES 1. Blanton L, Alabi N, Mustaquim D, et al. Update: Influenza Activity in the United States During the 2016–17 Season and Composition of the 2017–18 Influenza Vaccine. MMWR Morb Mortal Wkly Rep 2017; 66. 2. Narasaraju T, Yang E, Samy RP, et al. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol 2011; 179:199-210. 3. Short KR, Kroeze EJ, Fouchier RA, and Kuiken T. Pathogenesis of influenza-induced acute respiratory distress syndrome. Lancet Infect Dis 2014; 14:57-69. 4. Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, and Straus SE. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. J Clin Invest 1998; 101:643-9. 5. Busch-Petersen J, Carpenter DC, Burman M, et al. Danirixin: A Reversible and Selective Antagonist of the CXC Chemokine Receptor 2. J Pharmacol Exp Ther 2017; 362:338-346. 6. Washburn,M, Crosby R, Remlinger K, Wang F, and Creech D. Therapeutically Attenuating Neutrophil Recruitment with a CXCR2 Antagonist in Combination with Oseltamivir Ameliorates Influenza Induced Lung Injury and Disease. OFID (i accepted for publication, OFID-D-18-00689) 7. Miller BE, Mistry S, Smart K, et al. The pharmacokinetics and pharmacodynamics of danirixin (GSK1325756) − a selective CXCR2 antagonist − in healthy adult subjects. BMC Pharmacology and Toxicology 2015; 16:18. 8. Roberts G, Chen S, Yates P, et al. Tandomized, Double-Blind, Placebo-Controlled Study of the Safety, Tolerability and Clinical Effect of Danirixin i)n Adults with Acute, Uncomplicated Influenza. OFID (accepted for publication, OFID-D 18-0069) 9. Lazaar AL, Miller BE, Tabberer M, et al. Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD. European Respiratory Journal 2018. Page 16 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 10. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, and Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348:g2545. 11. European Centre for Disease Prevention and Control. Influenza in Europe, Season 2016– 2017. 2017 [cited 2018 February 28]; Available from: https://ecdc.europa.eu/en/publications- data/influenza-europe-season-2016-2017. 12. Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011; 60:1-24. 13. McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis 2007; 45:1568-75. 14. Lee N, Choi KW, Chan PK, et al. Outcomes of adults hospitalised with severe influenza. Thorax 2010; 65:510-5. 15. de Jong MD, Ison MG, Monto AS, et al. Evaluation of intravenous peramivir for treatment of influenza in hospitalized patients. Clin Infect Dis 2014; 59:e172-85. 16. Marty FM, Vidal-Puigserver J, Clark C, et al. Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. Lancet Respir Med 2017; 5:135-146. 17. Garg S, Jain S, Dawood FS, et al. Pneumonia among adults hospitalized with laboratory- confirmed seasonal influenza virus infection-United States, 2005-2008. BMC Infect Dis 2015; 15:369. 18. Jurcevic S, Humfrey C, Uddin M, Warrington S, Larsson B, and Keen C. The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions. Br J Clin Pharmacol 2015; 80:1324-36. 19. Moss RB, Mistry SJ, Konstan MW, et al. Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J Cyst Fibros 2013; 12:241-8. Page 17 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 20. Thatcher TH, McHugh NA, Egan RW, et al. Role of CXCR2 in cigarette smoke-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol 2005; 289:L322-8. 21. Miller BE, Smart K, Mistry S, et al. The pharmacokinetics of conventional and bioenhanced tablet formulations of danirixin (GSK1325756) following oral administration in healthy, elderly, human volunteers. Eur J Drug Metab Pharmacokinet 2014; 39:173-81. Page 18 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 TABLES AND FIGURES Table 1. Clinical Response in the Influenza Positive Population Placebo + Danirixin Danirixin oseltamivir 15 mg + 50 mg + 75 mg (n=2) oseltamivir oseltamivir a b 75 mg (n=4) 75 mg (n=4) Clinical Response, n 2 4 4 Yes, n (%) 2 (100) 4 (100) 4 (100) Hospital discharge due to clinical 0 1 (25) 2 (50) improvement, n (%) Hospital discharge as 24-hr 1 (50) 2 (50) 1 (25) confirmation, n (%) Vital signs resolved, n (%) 1 (50) 1 (25) 1 (25) Clinical Outcome, n 2 4 4 Clinical improvement, n (%) 2 (100) 4 (100) 4 (100) Kaplan–Meier Estimate, n 2 3 4 Median, days 1.33 4.53 4.76 95% confidence interval 0.71, 1.95 2.95, 5.71 2.71, 5.25 25%–75% 0.71–1.95 2.95–5.71 3.66–5.08 One participant in the danirixin 15 mg + oseltamivir 75 mg group had vital sign resolution at baseline and was counted as having a clinical response but was not included in the Kaplan–Meier estimates. One participant in the danirixin 50 mg + oseltamivir 75 mg group received oseltamivir 30 mg. Hospital discharge due to clinical improvement served as 24-hour confirmation for the clinical response. Page 19 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Table 2. Respiratory Response in the Influenza Positive Population Placebo + Danirixin Danirixin oseltamivir 15 mg + 50 mg + 75 mg (n=2) oseltamivir oseltamivir 75 mg (n=4) 75 mg (n=4) Positive Respiratory Response, n 2 4 4 Yes, n (%) 1 (50) 2 (50) 2 (50) Respiratory rate ≤24/min 0 0 0 (without supplemental oxygen) Return to no requirement of supplemental 1 (50) 2 (50) 2 (50) oxygen, n (%) Return to pre-morbid oxygen 0 0 0 (participants with chronic oxygen use) One participant in the danirixin 50 mg + oseltamivir 75 mg group received oseltamivir 30 mg. Page 20 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Table 3. Adverse Events Reported by Overall Frequency in the Safety Population Preferred Term Placebo + Danirixin Danirixin Total oseltamivir 15 mg + 50 mg + (N=10) 75 mg (n=2) oseltamivir oseltamivir 75 mg (n=4) 75 mg (n=4) Any event, n (%) 0 4 (100) 4 (100) 8 (80) Asthma 0 1 (25) 0 1 (10) Atelectasis 0 0 1 (25) 1 (10) Bronchitis 0 0 1 (25) 1 (10) Cardiac failure 0 0 1 (25) 1 (10) Chills 0 0 1 (25) 1 (10) COPD 0 0 1 (25) 1 (10) Clostridium difficile infection 0 0 1 (25) 1 (10) Contusion 0 1 (25) 0 1 (10) Cough 0 1 (25) 0 1 (10) Dyspnea 0 0 1 (25) 1 (10) Fungal infection 0 0 1 (25) 1 (10) Hemoglobin decreased 0 0 1 (25) 1 (10) Hyperglycemia 0 1 (25) 0 1 (10) Hypokalemia 0 0 1 (25) 1 (10) Infusion-site extravasation 0 0 1 (25) 1 (10) Monocytosis 0 0 1 (25) 1 (10) Pneumonia bacterial 0 1 (25) 0 1 (10) Sinusitis 0 0 1 (25) 1 (10) Vertigo 0 1 (25) 0 1 (10) One participant in the danirixin 50 mg + oseltamivir 75 mg group received oseltamivir 30 mg. COPD, chronic obstructive pulmonary disease. Page 21 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Figure Legend Figure 1. (A) Study Design and (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, encephalitis). CrCL, 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 B C D EL-NE, specific fragment human neutrophil elastase mediated degradation of elastin, IL8, interleukin (IL)-8; IP10, inducible protein (IP)-10 Page 22 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Figure 1 Page 23 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz163/5426498 by Ed 'DeepDyve' Gillespie user on 09 April 2019 Figure 2 Page 24 Accepted Manuscript

Journal

Open Forum Infectious Diseases – Oxford University Press

Published: Apr 3, 2019

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