Intravenous peramivir vs oral oseltamivir in high‐risk emergency department patients with influenza: Results from a pilot randomized controlled study

Abstract Background Peramivir offers a single‐dose intravenous (IV) treatment option for influenza (vs 5‐day oral dosing for oseltamivir). We sought to compare outcomes of emergency department (ED) patients at high risk for influenza complications treated with IV peramivir vs oral oseltamivir. Methods During the 2015‐16 and 2016‐17 influenza seasons, adult patients in two US EDs were randomized to either oral oseltamivir or IV peramivir treatment group. Eligibility included positive molecular influenza test; met CDC criteria for antiviral treatment; able to provide informed consent and agree to follow‐up assessment. Outcomes were measured by clinical end‐point indicators, including FLU‐PRO Score, Ordinal Scale, Patient Global Impression on Severity Score, and Karnofsky Performance Scale for 14 days. Non‐inferior t test was performed to assess comparative outcomes between the two groups. Results Five hundred and seventy‐five (68%) of 847 influenza‐positive patients were approached. Two hundred and eighty‐four met enrollment criteria and 179 were enrolled; of these 95 (53%) were randomized to peramivir, and 84 to oseltamivir. Average FLU‐PRO score at baseline was similar (peramivir: 2.67 vs oseltamivir: 2.52); the score decreased over time for both groups (day 5: peramivir: 1.71 vs oseltamivir: 1.62; day 10: peramivir: 1.48 vs oseltamivir: 1.37; day 14: peramivir: 1.40 vs oseltamivir: 1.33; all P < .05 for significantly non‐inferior). Influenza‐related complications were similar between two groups (All: peramivir: 31% vs oseltamivir: 21%, P > .05; pneumonia: peramivir: 11% vs oseltamivir: 14%, P > .05). Conclusions Clinical outcomes of influenza‐infected patients treated with single‐dose IV peramivir were comparable to those treated with oral oseltamivir, suggesting potential utility of peramivir for influenza‐infected patients in the ED.


| INTRODUC TI ON
Seasonal influenza causes up to 959 000 hospitalizations and 79 400 deaths in the United States annually since 2010. [1][2][3] As the frontline of the health care system, emergency departments (EDs) see up to three quarter of a million patients during each influenza season. 4,5 The Centers for Disease Control and Prevention (CDC) recommends that people infected with influenza should receive antiviral treatment, to decrease the occurrence of severe complications and shorten the course of illness, especially for those at high risk of influenza complications. This includes young children, adults 65 years of age and older, pregnant women, and people with certain co-morbid medical conditions. 6,7 Currently, there are four Food and Drug Administration (FDA)-approved antiviral drugs for treatment of influenza, including three influenza virus neuraminidase inhibitor (oseltamivir, zanamivir, and peramivir) and one polymerase acidic protein inhibitor (baloxavir). 8 Since the 2003-2004 influenza season, oseltamivir has been the predominant antiviral drug used for ambulatory care patients, including those who come to the US EDs, with a diagnosis of influenza. 9 However, requirement for a 5 day, twice a day oral dosing regimen, make alternate antiviral drugs more appealing for both clinicians and patients, particularly those seen in acute care setting such as EDs, where filling and adhering with medications is well known to be challenging. Several alternative, single-dose medication options remain under investigation for ED use, but each has limitations. Zanamivir, which exists as a powder in an inhaled form in the United States, has similar efficacy to oseltamivir, but it is not generally recommended for people with asthma or chronic obstructive pulmonary disease according to CDC 8 ; baloxavir which was recently approved in the United States by FDA in October 24, 2018, 10 15 months after the end of our study, is restricted to use in those >12 years old and has not been studied in those >65 years old, pregnant, or lactating women. 8 In addition, there are concerns of rapid emergence of resistance to the use of baloxavir. 11,12 These leaves peramivir, which can be used in patients ≥2 years old, as a potential favorable alternative candidate antiviral drug for treating ED patients with influenza.
Peramivir, a neuraminidase inhibitor agent with the same mechanism of action as oseltamivir, has been demonstrated to have activity against both influenza A and B viruses, and shorten duration of influenza symptoms for outpatient adults with uncomplicated influenza. 13,14 Several studies previously demonstrated both safety and non-inferiority of peramivir hospitalized patients and outpatients with influenza. 13,15,16 A multinational, multicenter, double-blind randomized trial in East Asia showed that the duration of influenza symptoms in adult influenza-infected patients treated with a single dose of 300 mg of IV peramivir, or 600 mg of peramivir was non-inferior to that treated with 5-day twice a day oseltamivir. The incidence of severe adverse events by peramivir was similar to oseltamivir. 13 de Jong and colleagues conducted a trial in hospitalized patients with suspected influenza randomized to 5-day treatment with intravenous peramivir (600 mg once daily) or placebo; all received the institution's standard of care treatment. That also showed that no difference in median time to clinical resolution between the two groups. However, there was a trend toward a shorter time to clinical resolution in ≥4 of 5 vital sign abnormalities (temperature, oxygen saturation, respiration rate, heart rate, and systolic blood pressure) for 24 hours, among those who required intensive care who received peramivir (vs oseltamivir). 16 In another small randomized trial of 92 adult inpatients and outpatients with high-risk factors, the results also showed that patients treated with single-dose 600 mg peramivir had similar outcomes with regard to time to reduce fever, total symptom scores, and virus titer as compared to those treated with orally administrated oseltamivir (75 mg, twice per day for 5 days). 15 Accordingly, CDC includes peramivir as a recommended agent, which can be administered intravenously which should be considered for patients who cannot tolerate or absorb orally or enterically administered oseltamivir. 7 Given that only one-dose via intravenous (IV) is required for use of peramivir for influenza treatment, the agent might be a welcome alternate antiviral in acute episodic setting such as EDs; further during future influenza seasons (or during a pandemic) it is possible that selectively increased resistance to oseltamivir (vs peramivir) could occur. 17 To date, there are no studies comparing the outcome of ED patients treated with peramivir vs oseltamivir patients considered at high risk for influenza complications.
We sought to determine the outcomes and safety of peramivir vs oseltamivir in patients diagnosed in the ED with influenza, who are at high risk for influenza complications according to CDC risk criteria. Data for this analysis were collected from a pilot randomized controlled trial intended to evaluate the practical feasibility of enrolling subjects for influenza therapeutic trials in the ED setting. The outcomes of antiviral treatment were measured using several clinical end-point indicators, including FLU-PRO Score, Ordinal Scale, Patient Global Impression on Severity (PGIS) Score, and Karnofsky Performance Scale, collected via patient's daily diaries and phone follow-ups. written informed consent to patients who were eligible and expressed interested in participating, explaining the risks and benefits of the study to the patient and ensuring that the patient understood all aspects of the study (study coordinators were present with the physician, to assist where needed). Consented patients were randomized to oral oseltamivir or IV peramivir treatment group using an internet-based computerized randomization system (www.random. org) without a block randomization design but with an intent of 1:1 ratio. The random number generated for each consented patient was an independent event and independent by site. The randomization was not stratified by the study site. Since this study was intended to evaluate the practical feasibility of enrolling subjects for influenza therapeutic trials in the ED setting, the sample size of 50-150 subjects sample size was determined in collaboration with the funder (Department of Health and Human Services Office of the Assistant

Secretary for Preparedness and Response/Biomedical Advanced
Research and Development Authority) to be adequate for this pilot effort which is being conducted specifically to examine the feasibility of achieving higher recruitment rates than has historically been achieved in other clinical venues, and the ability to reliably collect useful therapeutic end-point data from an ED enrollment site.
Both oseltamivir and peramivir were dosed based on creatinine clearance (CrCl) results which was calculated using the Cockcroft Gault equation; 30 mg once daily, 30 mg twice daily or 75 mg twice daily of oseltamivir for 5 days or 100 mg, 200 mg, 600 mg of onetime IV peramivir. Both groups received the first dose of antiviral treatment in the ED following randomization. For the oseltamivir group, patients were instructed to take the remaining doses on the subsequent 4 days, either inpatient or outpatient, based on disposition from the ED attending. For the peramivir group: for patients who were discharged from the ED, no further study drug was administered; for patients admitted to the hospital from the ED, the inpatient treating provider was given the option to choose to continue administering IV peramivir, based on their clinical discretion.
An investigator from the study team gave the inpatient treating provider information about the study, including information on how to continue IV peramivir at the same dose for each subsequent day for up to 4 days. If a participant remained in the hospital beyond 5 days of treatment, and the patient was symptomatically better, treatment stopped. If the patient remained hospitalized after 5 days of treatment and had not improved, the treating provider was given the option to continue IV peramivir daily for another 5-day course (with consultation as requested from a 24/7 on-call infectious disease specialist and pharmacist, to assist with decision-making). Treatment with peramivir was discontinued upon discharge from the hospital for all participants in the IV peramivir arm.
As a secondary objective, we created a repository of residual nasopharyngeal samples from ED patients with suspected influenza illness for purposes of future laboratory analysis of new assays with potential interest for characterizing patients with influenza.
Specimens were collected by clinical staff at day 1 (baseline) according to standard of care practice and at day 3 (under a research protocol) using a flocked swab and universal viral transport media. Day 1 specimen was first testing for clinical purposes by Xpert Flu, and the remaining specimen was transported to, frozen and stored at the central study laboratory at JHH for future analysis. For the day 3 specimen, the entire specimen was transported to, frozen and stored at the central laboratory at JHH for future analysis (see below). The study was approved by the IRB at each of the participating institutions. This study was registered as protocol: NCT02609399 at clinicaltrials.gov.
Outcomes of antiviral treatment were measured by the validated FLU-PRO score, 18 a 32-question clinical end-point indicator (scale 1-5 for each question) from enrollment (day 1) for 14 days via patients' daily diary. Influenza disease severity was also assessed by PGIS, whereby participants rated their influenza symptoms ranging from no symptom (score 0), mild symptoms (1), moderate symptoms (2), or severe symptoms (3) at the time of enrollment, day 7 and 28. 19,20 Clinical status of the participants was evaluated by a validated 6-step Ordinal Scale (1-6) from the day of ED or hospital discharge as: return to normal activities, 1 point; discharged but not back to normal activities, 2 points; Non-ICU hospitalization, 3 points; ICU without mechanical ventilation, 4 points; ICU with mechanical ventilation/ ECMO, 5 points; and death, 6 points. 21 For any patient who was discharged where the status of back to normal activities was unknown for any particular day, the Ordinal Scale for that day was conservatively coded as "2 points". If the patient reported returning to normal activities the previous day, and reported normal activities the day after then the Ordinal Scale was coded as "1 point". Physical function of the participants was assessed for 14 days by daily diary reports using the Karnofsky Performance Scale, which ranges from 0 to 100, with higher scores indicating better performance status. 22 For this pilot feasibility phase of the study, all of follow-ups after the participant's discharge from the ED or hospital were conducted by study coordinators by phone.
We evaluated specimens from our biorepository for any patients in whom we were able to collect paired nasopharyngeal swab specimens (at both day 1 and 3) using a feature of the Cepheid GeneXpert® Xpress Flu/RSV real-time PCR assay which permitted us to assess the cycle threshold (C t ) values, as a semi-quantitative approach to infer influenza viral load from any particular sample.
Analysis of C t values using this approach was demonstrated previously to inversely reflect the amount of influenza viral RNA present in the sample. 23 A C t value of 40 for influenza A or B viruses was considered as an undetectable viral load for influenza A or B virus, respectively.  for each outcome of antiviral treatment by each time point, using the same approach described above. All data analyses were based on intent-to-treat analysis.

| RE SULTS
Overall, 847 patients with laboratory-confirmed influenza were seen at the ED sites during the study period. Among them, 575 (68%) were approached by the study coordinator, 284 (49%) of those met study enrollment criteria. Among those eligible, 186 (65%) provided consent, and 180 were enrolled and randomized (Figure 1). After excluding one patient who was determined to be ineligible following   Regarding patients with more than one CDC high-risk factor for an influenza complication, they did not fare worse than those with only one factor by either group in the PGIS score and the Ordinal Scale score by day. However, they reported their physical activities were worse than those with only one factor in the Karnofsky performance scale by both treatment groups in most of days followed

| D ISCUSS I ON
In this first ED-based randomized controlled influenza therapeutic clinical trial that fully enrolled, randomized, and initiated antiviral treatment intervention in EDs to compare outcomes of patients treated with IV peramivir vs a 5 day of oral oseltamivir, we found that the regimens were similar with regard to patient's self-reported relief of influenza symptoms, reduction of functional impairment, as well as the rates of adverse and severe adverse events, for influenzainfected CDC categorized "high-risk" patients. Consistent with prior peramivir vs oseltamivir randomized trials in hospitalized or outpatients, our trial in ED patients provides similar findings with regard to the clinical efficacy and safety of the use of single-dose IV peramivir. 13,15,16 To the best of our knowledge, this study provides the first evidence-based findings for use of IV peramivir in patients who present to an ED setting. As the majority of patients who are considered high risk for influenza complications receive intravenous lines as part of their ED care, the added burden of administration of IV peramivir would be unlikely to have a significant negative effect on ED staff work burden, or ED patient flow.  : 84  72  68  64  69  63  65  59  54  54  57  56  55  55  Peramivir:  92  85  74  77  72  74  68  72  68  70  74  62  69  65 In this study, we employed several validated symptom, disease severity, clinical, and physical functionality indexes to evaluate the outcomes associated with peramivir and oseltamivir treatment. All of them pointed to the same conclusion, namely that influenza symptoms were mitigated, disease severity decreased, and clinical and physical functionality improved over time with single-dose IV peramivir administered in the ED; further these outcomes were functionally similar to those observed among the group treated with a 5-day course regimen of oseltamivir. This finding, supports findings from previously observational studies conducted in non-ED studies, 13,15,16 but also provides important direct data for ED clinicians, to support consideration of single-dose treatment for influenza-infected patients at increased risk for influenza-related complications as an alternative to oral oseltamivir.
Given the busy, episodic nature of the ED, and the fact that compliance with medications at the time of discharge in some ED populations may be challenging, this additional therapeutic option may be appealing to ED providers and patients. It is important to note, however, that the current costs of peramivir are 6-time higher than a 5-day course of oseltamivir. 24 Further investigations are thus warranted, taking into account issues of adherence to oseltamivir, and assessment of other factors that could be impacted by treatment compliance, including emergence of resistant strains and spread of partially treated disease in the community.
As noted above, one of the potential advantages of the use of a single-dose regimen of antiviral medication for influenza treatment, is that patients might be less likely to adhere to a multiple-day multiple dosages (eg, 5-day course of oseltamivir). 25 Our data upheld this con- thus provide added potential value for the population, which would be particularly important during a pandemic.
Of note, more than 50% of our enrollees reported onset of the respiratory symptoms more than 48 hours before coming to the ED, consistent with our previous study, as well as others ED-based studies. 28,29 Our results demonstrate that antiviral treatment for those with greater than 2 days of symptoms also benefit from therapy in One of the important features of our study is that we recruited a substantial numbers of minority influenza-infected patients to this randomized controlled trial. Approximately, two-thirds (67%) of participants were African American and 16% were Hispanic ethnicity.
Studies have documented racial and ethnic disparity regarding influenza vaccination and influenza-related hospitalization. 30 of peramivir in treating high-risk ED patients with influenza, as the primary aim of the study was to determine the feasibility of conducting influenza-related therapeutic clinical trials in the ED setting.
Second, the outcomes of antiviral treatment might be influenced by the virulence of influenza virus as well as its antiviral resistance level by each influenza season. However, we did not set out, to do further subtyping and/or characterization of antiviral resistance for this study. Third, even though self-reported treatment outcome measures that we used have been validated, information bias, rooted in self-reported data could have differentially occurred between the antiviral treatment groups. Fourth, some information (eg, duration and amount of antipyretic use) which might be associated the outcome of antiviral treatment was not collected during the trial. We were thus not able to assess the impact of these variables since we were not able to go back to collect that information. Fifth, our evaluation of influenza viral loads before and after administration of antivirals for this study used stored aliquoted samples, which could have suffered from degradation of the archived samples, especially for those with low viral load. Finally, it is also possible to have biases arising from missing data in the patient daily diary reports, and loss to follow-ups in this study.
In conclusion, in this ED randomized controlled clinical trial, we found the clinical and physical functionality outcomes of one-dose IV-administered peramivir was comparable to 5-day course oral oseltamivir for CDC-defined "high-risk" influenza patients. Influenzarelated complications were minimal and side effects relevant to antiviral medication were mild and infrequent in both groups. While further cost-effectiveness studies are required, ED clinicians should consider the option of single-dose IV-administered peramivir for treating influenza-infected ED patients, especially those who already have intravenous lines in place.

ACK N OWLED G EM ENTS
The ED National Influenza Network Investigators: Maricopa: Mary Mulrow, RN.

CO N FLI C T O F I NTE R E S T
RER reports personal fees from Cepheid Inc, grants from Cepheid Inc, during the conduct of the study; personal fees from Roche Molecular, grants from Janssen, and grants from Cepheid, Inc, outside the submitted work. All other authors report no potential conflicts.